VCV000004611.12 - ClinVar

NM_032383.5(HPS3):c.2482-2A>G

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032383.5(HPS3):c.2482-2A>G

Variation ID: 4611 Accession: VCV000004611.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q24 3: 149163840 (GRCh38) [ NCBI UCSC ] 3: 148881627 (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	Apr 4, 2013	Jun 17, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032383.5:c.2482-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001308258.2:c.1987-2A>G		splice acceptor
NC_000003.12:g.149163840A>G
NC_000003.11:g.148881627A>G
NG_009847.1:g.39257A>G
NG_011800.3:g.63206T>C
LRG_563:g.39257A>G
LRG_563t1:c.2482-2A>G

... more HGVS ... less HGVS

Protein change

Other names

2621-2A-G

Canonical SPDI

NC_000003.12:149163839:A:G

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA340271 OMIM: 606118.0004 dbSNP: rs397507168 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 11590544 to determine the location of this allele on the current reference sequence. Their numbering is based on AY033141.1, with the first nt as 0.

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.
CP		-	-	GRCh38 GRCh37	636	993
HPS3		-	-	GRCh38 GRCh37	947	1304

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.
Hermansky-Pudlak syndrome 3	Pathogenic (2)	criteria provided, single submitter	Jan 30, 2024	RCV000004874.8
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 29, 2022	RCV001384936.7
Hermansky-Pudlak syndrome	Pathogenic (1)	no assertion criteria provided	Jun 18, 2021	RCV001831513.1

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 29, 2022)	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: SCV001584631.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 11590544‚ 16199547 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 4611). This variant is also known as 2621-2A>G. Disruption of this splice site has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 11590544). This variant is present in population databases (rs397507168, gnomAD 0.002%). This sequence change affects an acceptor splice site in intron 13 of the HPS3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HPS3 are known to be pathogenic (PMID: 11590544). (less)
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hermansky-Pudlak syndrome 3 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005059717.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Nov 01, 2001)	no assertion criteria provided Method: literature only	HERMANSKY-PUDLAK SYNDROME 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025050.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016	Publications: PubMed (1) PubMed: 11590544 Comment on evidence: For discussion of the splice site mutation in the HPS3 gene (2621-2A-G) that was found in compound heterozygous state in patients with Hermansky-Pudlak syndrome (HPS3; … (more) For discussion of the splice site mutation in the HPS3 gene (2621-2A-G) that was found in compound heterozygous state in patients with Hermansky-Pudlak syndrome (HPS3; 614072) by Huizing et al. (2001), see 606118.0002. (less)
Pathogenic (Jun 18, 2021)	no assertion criteria provided Method: clinical testing	Hermansky-Pudlak syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002081519.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 4611). This variant is also known as 2621-2A>G. Disruption of this splice site has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 11590544). This variant is present in population databases (rs397507168, gnomAD 0.002%). This sequence change affects an acceptor splice site in intron 13 of the HPS3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HPS3 are known to be pathogenic (PMID: 11590544).

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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.	Huizing M	American journal of human genetics	2001	PMID: 11590544

Text-mined citations for rs397507168 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_032383.5(HPS3):c.2482-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507168 ...