VCV000215324.42 - ClinVar

NM_001953.4(TYMP):c.929-6_929-3del

Germline

Classification

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.

(16)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001953.4(TYMP):c.929-6_929-3del

Variation ID: 215324 Accession: VCV000215324.42

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 22q13.33 22: 50526479-50526482 (GRCh38) [ NCBI UCSC ] 22: 50964908-50964911 (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	Oct 11, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001953.5:c.929-6_929-3del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001953.5:c.929-6_929-3delCCGC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001113755.3:c.929-6_929-3del		intron variant
NM_001113756.3:c.929-6_929-3del		intron variant
NM_001257988.1:c.929-6_929-3del		intron variant
NM_001257989.1:c.929-6_929-3del		intron variant
NM_001257989.1:c.929-6_929-3delCCGC		intron variant
NM_001953.4:c.929-6_929-3del
NC_000022.11:g.50526480CGGG[1]
NC_000022.10:g.50964909CGGG[1]
NG_011860.1:g.8600CCGC[1]
NG_016235.1:g.4954CCGC[1]
NG_021419.1:g.23265CGGG[1]
NG_202277.1:g.801CGGG[1]
LRG_727:g.8600CCGC[1]
LRG_727t1:c.929-6_929-3del
LRG_727t2:c.929-6_929-3del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000022.11:50526478:GCGGGCGGG:GCGGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00719 (GCGGG)

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA324652 dbSNP: rs201685922 VarSome

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
Gene	OMIM	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.
LOC130067862	-	-	-	GRCh38	-	490
SCO2		-	-	GRCh38 GRCh37	4	884
TYMP		-	-	GRCh38 GRCh37	460	1108

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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 17, 2023	RCV000200098.19
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000224802.32
Mitochondrial complex IV deficiency, nuclear type 1	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000293978.14
Fatal Infantile Cardioencephalomyopathy	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000374728.14
Mitochondrial DNA depletion syndrome 1	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Sep 13, 2023	RCV000404575.25
Mitochondrial neurogastrointestinal encephalomyopathy	Benign (1)	no assertion criteria provided	Dec 26, 2019	RCV001272325.10

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.
Benign (Jan 07, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252447.3 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: The variant is found in MITONUC-MITOP,MITO24,DEPLTN-MITOP panel(s).
Benign (Aug 19, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280855.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Benign (Feb 19, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000308569.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Fatal Infantile Cardioencephalomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000484004.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Mitochondrial Neurogastrointestinal Encephalopathy Disease Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000439327.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Mitochondrial Respiratory Chain Complex IV Deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000484005.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Mar 06, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790104.1 First in ClinVar: Jan 26, 2017 Last updated: Jan 26, 2017	Publications: PubMed (1) PubMed: 10852545
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141458.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Feb 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003844900.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Variant summary: TYMP c.929-6_929-3delCCGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered … (more) Variant summary: TYMP c.929-6_929-3delCCGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 150776 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) phenotype (0.0011), strongly suggesting that the variant is benign. ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=9), as uncertain significance (n=1) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001022394.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Benign (Sep 13, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158819.3 First in ClinVar: Feb 09, 2020 Last updated: Feb 20, 2024
Benign (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 1 Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812642.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: European Non-Finnish population allele frequency is 1.460% (rs201685922, 1045/67956 alleles, 12 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, … (more) European Non-Finnish population allele frequency is 1.460% (rs201685922, 1045/67956 alleles, 12 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 (less)
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821140.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: TYMP: BP4, BS1, BS2 Number of individuals with the variant: 34
Benign (Dec 26, 2019)	no assertion criteria provided Method: clinical testing	Mitochondrial neurogastrointestinal encephalomyopathy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454200.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jan 14, 2016)	Flagged submission flagged submission Method: literature only Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Mitochondrial DNA depletion syndrome 1 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000264564.1 First in ClinVar: Mar 05, 2016 Last updated: Mar 05, 2016	Publications: PubMed (1) PubMed: 10852545 Other databases http://www.ncbi.nlm.nih.gov/book… http://www.ncbi.nlm.nih.gov/books/NBK1179/
Uncertain significance (Oct 16, 2015)	Flagged submission flagged submission (DGD Variant Analysis Guidelines) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257781.5 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Variant summary: TYMP c.929-6_929-3delCCGC alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 150776 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in TYMP causing Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) phenotype (0.0011), strongly suggesting that the variant is benign. ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=9), as uncertain significance (n=1) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.

Comment:

European Non-Finnish population allele frequency is 1.460% (rs201685922, 1045/67956 alleles, 12 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mitochondrial Neurogastrointestinal Encephalopathy Disease.	Adam MP	-	2016	PMID: 20301358
Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.	Nishino I	Annals of neurology	2000	PMID: 10852545

Text-mined citations for rs201685922 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001953.4(TYMP):c.929-6_929-3del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201685922 ...