ClinVar Genomic variation as it relates to human health
NM_004656.4(BAP1):c.944A>C (p.Glu315Ala)
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.
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.
Uncertain significance(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004656.4(BAP1):c.944A>C (p.Glu315Ala)
Variation ID: 412406 Accession: VCV000412406.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.1 3: 52405282 (GRCh38) [ NCBI UCSC ] 3: 52439298 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 17, 2017 Feb 14, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004656.4:c.944A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004647.1:p.Glu315Ala missense NC_000003.12:g.52405282T>G NC_000003.11:g.52439298T>G NG_031859.1:g.9712A>C LRG_529:g.9712A>C LRG_529t1:c.944A>C - Protein change
- E315A
- Other names
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- Canonical SPDI
- NC_000003.12:52405281:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00014
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
1000 Genomes Project 30x 0.00031
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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BAP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2713 | 2729 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000472838.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 5, 2024 | RCV000565342.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV001562013.4 |
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
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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
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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. |
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Uncertain significance
(Jun 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV001737437.2
First in ClinVar: Jun 19, 2021 Last updated: Jun 23, 2021 |
Comment:
The BAP1 c.944A>C (p.Glu315Ala)missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/3-52439298-T-G?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign … (more)
The BAP1 c.944A>C (p.Glu315Ala)missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/3-52439298-T-G?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in individuals with renal cell carcinoma, malignant mesothelioma, and pediatric osteosarcoma (PMID: 31034483, 28687356, 26580448). It is present 2X in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/variant/3-52439298-T-G). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. (less)
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Likely benign
(Aug 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000672775.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001784714.4
First in ClinVar: Aug 14, 2021 Last updated: Mar 11, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of renal cancer, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of renal cancer, osteosarcoma, or mesothelioma (Zhang 2015, Betti 2017, Christensen 2019); This variant is associated with the following publications: (PMID: 21642991, 26659599, 28687356, 26580448, 31034483, 34711244) (less)
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Uncertain significance
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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BAP1-related tumor predisposition syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000553932.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 315 of the BAP1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 315 of the BAP1 protein (p.Glu315Ala). This variant is present in population databases (rs149974450, gnomAD 0.02%). This missense change has been observed in individual(s) with renal cell carcinoma and malignant pleural mesothelioma (PMID: 28687356, 31034483). ClinVar contains an entry for this variant (Variation ID: 412406). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAP1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000682659.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with alanine at codon 315 of the BAP1 protein. Computational prediction tool suggests that this variant may not impact … (more)
This missense variant replaces glutamic acid with alanine at codon 315 of the BAP1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual each affected with malignant pleural mesothelioma (PMID: 28687356) and an individual affected with renal cell carcinoma (PMID: 31034483). This variant has also been identified in 26/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and reported in two individuals over age 70 without cancer (FLOSSIES). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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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. |
Citations for germline classification of this variant
HelpText-mined citations for rs149974450 ...
HelpRecord last updated Feb 20, 2024
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.