Variant summary: RNU4ATAC n.51G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00043 in 130510 control chromosomes. n.51G>A has been reported in the literature in multiple individuals affected with Microcephalic osteodysplastic primordial dwarfism, type I or Roifman Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21474760, 26522830). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NR_023343.3(RNU4ATAC):n.51G>A
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(15)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NR_023343.3(RNU4ATAC):n.51G>A
Variation ID: 30178 Accession: VCV000030178.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q14.2 2: 121530930 (GRCh38) [ NCBI UCSC ] 2: 122288506 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 15, 2018 Dec 22, 2024 Nov 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001395891.1:c.196-605C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001142273.2:c.196-605C>T intron variant NM_001142274.2:c.196-605C>T intron variant NM_001207051.2:c.196-605C>T intron variant NM_001378003.1:c.196-605C>T intron variant NM_001378004.1:c.196-605C>T intron variant NM_001378005.1:c.196-605C>T intron variant NM_015282.3:c.196-605C>T intron variant NR_023343.3:n.51G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.121530930G>A NC_000002.11:g.122288506G>A NG_029832.1:g.5051G>A LRG_1202:g.5051G>A LRG_1202t1:n.51G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000002.12:121530929:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00043
Exome Aggregation Consortium (ExAC) 0.00046
Trans-Omics for Precision Medicine (TOPMed) 0.00057
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00038
- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CLASP1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
81 | 351 | |
| RNU4ATAC | - | - |
GRCh38 GRCh37 |
1 | 267 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 19, 2024 | RCV000023096.15 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 9, 2023 | RCV000202312.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 2, 2015 | RCV001255662.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2022 | RCV002482901.4 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2024 | RCV001596939.26 | |
|
RNU4ATAC-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV003415730.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001832417.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021
Comment:
Patient analyzed with Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel
|
|
|
|
Pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934281.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: RNU4ATAC n.51G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00043 in 130510 control chromosomes. … (more)
Variant summary: RNU4ATAC n.51G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00043 in 130510 control chromosomes. n.51G>A has been reported in the literature in multiple individuals affected with Microcephalic osteodysplastic primordial dwarfism, type I or Roifman Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21474760, 26522830). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
maternal
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026349.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4_MOD, PP1, PS3, PM3
|
|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
RNU4ATAC-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004115105.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The RNU4ATAC n.51G>A is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, … (more)
The RNU4ATAC n.51G>A is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, and functional studies support its pathogenicity (He et al. 2011. PubMed ID: 21474760; Abdel-Salam et al. 2013. PubMed ID: 23794361; Merico et al. 2015. PubMed ID: 26522830; Farach et al. 2017. PubMed ID: 29265708; Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.063% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288506-G-A). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Osteodysplastic primordial dwarfism, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences
Accession: SCV001451936.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Clinical Features:
Microcephaly (present) , Seizure (present) , Dry skin (present) , Global developmental delay (present) , Simplified gyral pattern (present) , Corpus callosum, agenesis of (present)
Zygosity: Compound Heterozygote
Age: 0-9 years
Sex: female
Ethnicity/Population group: North Indian
Geographic origin: India
|
|
|
Likely pathogenic
(Feb 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Roifman syndrome
Affected status: yes
Allele origin:
germline
|
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739477.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
|
|
|
Pathogenic
(Jun 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070508.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
The non-coding variant, n.51G>A, has been described in gnomAD with an allele frequency of 0.054% in the South Asian sub-population (dbSNP rsrs181195449). This sequence change … (more)
The non-coding variant, n.51G>A, has been described in gnomAD with an allele frequency of 0.054% in the South Asian sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region. The n.51G>A is a known pathogenic sequence change and has been reported in multiple cases with microcephalic osteodysplastic primordial dwarfism either in the homozygous or compound heterozygous state (PMIDs: 21474760, 23794361, 32628740, 29265708, 27312855, 26522830). Functional studies have also demonstrated that this sequence change reduced U12-dependent splicing activity by 90% compared to wildtype (PMID:21474760). Based on this information this variant is being classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Osteodysplastic primordial dwarfism, type 1
Lowry-Wood syndrome Roifman syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002793874.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243422.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in … (more)
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs188343279, gnomAD 0.07%). This variant has been observed in individual(s) with RNU4ATAC-related conditions (PMID: 21474760, 26522830). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30178). Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760). This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Osteodysplastic primordial dwarfism, type 1
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005400655.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Clinical Features:
Microcephaly (present) , Corpus callosum, agenesis of (present) , Lissencephaly (present) , Fetal growth restriction (present) , Interhemispheric cyst (present)
|
|
|
Pathogenic
(Sep 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822684.15
First in ClinVar: Jan 21, 2023 Last updated: Dec 22, 2024 |
Comment:
RNU4ATAC: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Nov 02, 2015)
|
no assertion criteria provided
Method: literature only
|
MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044387.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a … (more)
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 51G-A variant within the nonprotein-coding RNU4ATAC gene. All parents were heterozygous. Haplotype analysis demonstrated that the 51G-A mutation represents a founder event in the Amish. This mutation was also found in homozygosity in an Australian patient of Maltese descent. This mutation is located within an important structural feature known as the 5-prime stem loop and was predicted to disrupt the snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype. Edery et al. (2011) identified the 51G-A mutation in RNU4ATAC in homozygosity in affected members from 4 consanguineous families from the Mediterranean basin and in an Indian individual whose parents were not known to be related. Additionally, 3 unrelated patients from nonconsanguineous families carried the mutation in compound heterozygosity (see 601428.0005 and 601428.0006). Roifman Syndrome In a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) originally reported by Gray et al. (2011), Merico et al. (2015) identified compound heterozygosity for the 51G-A transition in the RNU4ATAC gene (GenBank NR_023343) and a 16G-A transition (601428.0010), both of which involve highly conserved nucleotides in the 5-prime stem-loop critical region and the stem II region, respectively. Their unaffected parents were each heterozygous for 1 of the variants. Neither variant was found in the Complete Genomics database, but the 51G-A variant was present at a frequency of 0.0014 in the 1000 Genomes Project database and the 16G-A variant was present at a frequency of 0.0008 in the Wellderly study database. Lowry-Wood Syndrome In a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome (LWS; 226960), Farach et al. (2018) identified compound heterozygosity for the r.51G-A transition (r.51G-A, NR_023343.1) in the RNU4ATAC gene, and an r.5A-C transversion (601428.0016) within the stem II region. (less)
|
|
|
Pathogenic
(Nov 02, 2015)
|
no assertion criteria provided
Method: literature only
|
ROIFMAN SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000257312.4
First in ClinVar: Nov 22, 2015 Last updated: Sep 14, 2020 |
Comment on evidence:
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a … (more)
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 51G-A variant within the nonprotein-coding RNU4ATAC gene. All parents were heterozygous. Haplotype analysis demonstrated that the 51G-A mutation represents a founder event in the Amish. This mutation was also found in homozygosity in an Australian patient of Maltese descent. This mutation is located within an important structural feature known as the 5-prime stem loop and was predicted to disrupt the snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype. Edery et al. (2011) identified the 51G-A mutation in RNU4ATAC in homozygosity in affected members from 4 consanguineous families from the Mediterranean basin and in an Indian individual whose parents were not known to be related. Additionally, 3 unrelated patients from nonconsanguineous families carried the mutation in compound heterozygosity (see 601428.0005 and 601428.0006). Roifman Syndrome In a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) originally reported by Gray et al. (2011), Merico et al. (2015) identified compound heterozygosity for the 51G-A transition in the RNU4ATAC gene (GenBank NR_023343) and a 16G-A transition (601428.0010), both of which involve highly conserved nucleotides in the 5-prime stem-loop critical region and the stem II region, respectively. Their unaffected parents were each heterozygous for 1 of the variants. Neither variant was found in the Complete Genomics database, but the 51G-A variant was present at a frequency of 0.0014 in the 1000 Genomes Project database and the 16G-A variant was present at a frequency of 0.0008 in the Wellderly study database. Lowry-Wood Syndrome In a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome (LWS; 226960), Farach et al. (2018) identified compound heterozygosity for the r.51G-A transition (r.51G-A, NR_023343.1) in the RNU4ATAC gene, and an r.5A-C transversion (601428.0016) within the stem II region. (less)
|
|
|
Pathogenic
(Nov 02, 2015)
|
no assertion criteria provided
Method: literature only
|
LOWRY-WOOD SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001432227.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment on evidence:
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a … (more)
Microcephalic Osteodysplastic Primordial Dwarfism In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 51G-A variant within the nonprotein-coding RNU4ATAC gene. All parents were heterozygous. Haplotype analysis demonstrated that the 51G-A mutation represents a founder event in the Amish. This mutation was also found in homozygosity in an Australian patient of Maltese descent. This mutation is located within an important structural feature known as the 5-prime stem loop and was predicted to disrupt the snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype. Edery et al. (2011) identified the 51G-A mutation in RNU4ATAC in homozygosity in affected members from 4 consanguineous families from the Mediterranean basin and in an Indian individual whose parents were not known to be related. Additionally, 3 unrelated patients from nonconsanguineous families carried the mutation in compound heterozygosity (see 601428.0005 and 601428.0006). Roifman Syndrome In a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) originally reported by Gray et al. (2011), Merico et al. (2015) identified compound heterozygosity for the 51G-A transition in the RNU4ATAC gene (GenBank NR_023343) and a 16G-A transition (601428.0010), both of which involve highly conserved nucleotides in the 5-prime stem-loop critical region and the stem II region, respectively. Their unaffected parents were each heterozygous for 1 of the variants. Neither variant was found in the Complete Genomics database, but the 51G-A variant was present at a frequency of 0.0014 in the 1000 Genomes Project database and the 16G-A variant was present at a frequency of 0.0008 in the Wellderly study database. Lowry-Wood Syndrome In a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome (LWS; 226960), Farach et al. (2018) identified compound heterozygosity for the r.51G-A transition (r.51G-A, NR_023343.1) in the RNU4ATAC gene, and an r.5A-C transversion (601428.0016) within the stem II region. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Osteodysplastic primordial dwarfism, type 1
Affected status: yes
Allele origin:
unknown
|
Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432350.1
First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
PS4_MOD, PP1, PS3, PM3
Comment:
The RNU4ATAC n.51G>A is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, and functional studies support its pathogenicity (He et al. 2011. PubMed ID: 21474760; Abdel-Salam et al. 2013. PubMed ID: 23794361; Merico et al. 2015. PubMed ID: 26522830; Farach et al. 2017. PubMed ID: 29265708; Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.063% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288506-G-A). This variant is interpreted as pathogenic.
Comment:
The non-coding variant, n.51G>A, has been described in gnomAD with an allele frequency of 0.054% in the South Asian sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region. The n.51G>A is a known pathogenic sequence change and has been reported in multiple cases with microcephalic osteodysplastic primordial dwarfism either in the homozygous or compound heterozygous state (PMIDs: 21474760, 23794361, 32628740, 29265708, 27312855, 26522830). Functional studies have also demonstrated that this sequence change reduced U12-dependent splicing activity by 90% compared to wildtype (PMID:21474760). Based on this information this variant is being classified as pathogenic.
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs188343279, gnomAD 0.07%). This variant has been observed in individual(s) with RNU4ATAC-related conditions (PMID: 21474760, 26522830). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30178). Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760). This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). For these reasons, this variant has been classified as Pathogenic.
Comment:
RNU4ATAC: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: RNU4ATAC n.51G>A alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.00043 in 130510 control chromosomes. n.51G>A has been reported in the literature in multiple individuals affected with Microcephalic osteodysplastic primordial dwarfism, type I or Roifman Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 21474760, 26522830). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PS4_MOD, PP1, PS3, PM3
Comment:
The RNU4ATAC n.51G>A is a noncoding alteration. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with RNU4ATAC-related disorders, and functional studies support its pathogenicity (He et al. 2011. PubMed ID: 21474760; Abdel-Salam et al. 2013. PubMed ID: 23794361; Merico et al. 2015. PubMed ID: 26522830; Farach et al. 2017. PubMed ID: 29265708; Benoit-Pilven et al. 2020. PubMed ID: 32628740). This variant is reported in 0.063% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-122288506-G-A). This variant is interpreted as pathogenic.
Comment:
The non-coding variant, n.51G>A, has been described in gnomAD with an allele frequency of 0.054% in the South Asian sub-population (dbSNP rsrs181195449). This sequence change is located in the 5' stem loop critical region. The n.51G>A is a known pathogenic sequence change and has been reported in multiple cases with microcephalic osteodysplastic primordial dwarfism either in the homozygous or compound heterozygous state (PMIDs: 21474760, 23794361, 32628740, 29265708, 27312855, 26522830). Functional studies have also demonstrated that this sequence change reduced U12-dependent splicing activity by 90% compared to wildtype (PMID:21474760). Based on this information this variant is being classified as pathogenic.
Comment:
This variant occurs in the RNU4ATAC gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs188343279, gnomAD 0.07%). This variant has been observed in individual(s) with RNU4ATAC-related conditions (PMID: 21474760, 26522830). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30178). Functional studies have shown that this variant disrupts ncRNA function (PMID: 21474760). This variant is located within the 5' stem-loop region of the RNU4ATAC RNA, which includes the 15.5K binding site and is important for spliceosome assembly (PMID: 32628740). A significant number of disease-associated RNU4ATAC variants are found in this region (PMID: 32628740, 30368667). For these reasons, this variant has been classified as Pathogenic.
Comment:
RNU4ATAC: PM3:Very Strong, PS3:Moderate, PM2:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical interpretation of variants identified in RNU4ATAC, a non-coding spliceosomal gene. | Benoit-Pilven C | PloS one | 2020 | PMID: 32628740 |
| Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype. | Shelihan I | Human genetics | 2018 | PMID: 30368667 |
| The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. | Farach LS | American journal of medical genetics. Part A | 2018 | PMID: 29265708 |
| Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing. | Merico D | Nature communications | 2015 | PMID: 26522830 |
| Is Roifman syndrome an X-linked ciliopathy with humoral immunodeficiency? Evidence from 2 new cases. | Gray PE | International journal of immunogenetics | 2011 | PMID: 21977988 |
| Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. | Edery P | Science (New York, N.Y.) | 2011 | PMID: 21474761 |
| Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. | He H | Science (New York, N.Y.) | 2011 | PMID: 21474760 |
Text-mined citations for rs188343279 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence information reported in PubMed 21474760 Fig. 1B to determine the location of this allele on the current reference sequence.