rs149499021

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004656.4(BAP1):​c.2057-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00756 in 1,567,172 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0049 ( 8 hom., cov: 33)
Exomes 𝑓: 0.0078 ( 52 hom. )

Consequence

BAP1
NM_004656.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0004388
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:18

Conservation

PhyloP100: -0.666
Variant links:
Genes affected
BAP1 (HGNC:950): (BRCA1 associated protein 1) This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 3-52402425-C-A is Benign according to our data. Variant chr3-52402425-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240055.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=10, Likely_benign=5}. Variant chr3-52402425-C-A is described in Lovd as [Benign]. Variant chr3-52402425-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00491 (748/152332) while in subpopulation NFE AF= 0.00879 (598/68022). AF 95% confidence interval is 0.00821. There are 8 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 748 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BAP1NM_004656.4 linkc.2057-4G>T splice_region_variant, intron_variant Intron 16 of 16 ENST00000460680.6 NP_004647.1 Q92560A0A024R305

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BAP1ENST00000460680.6 linkc.2057-4G>T splice_region_variant, intron_variant Intron 16 of 16 1 NM_004656.4 ENSP00000417132.1 Q92560

Frequencies

GnomAD3 genomes
AF:
0.00491
AC:
748
AN:
152214
Hom.:
8
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00164
Gnomad AMI
AF:
0.0176
Gnomad AMR
AF:
0.00137
Gnomad ASJ
AF:
0.00490
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00879
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00454
AC:
803
AN:
176894
Hom.:
2
AF XY:
0.00471
AC XY:
447
AN XY:
94842
show subpopulations
Gnomad AFR exome
AF:
0.00192
Gnomad AMR exome
AF:
0.00103
Gnomad ASJ exome
AF:
0.00455
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00123
Gnomad FIN exome
AF:
0.00115
Gnomad NFE exome
AF:
0.00879
Gnomad OTH exome
AF:
0.00415
GnomAD4 exome
AF:
0.00785
AC:
11102
AN:
1414840
Hom.:
52
Cov.:
32
AF XY:
0.00783
AC XY:
5486
AN XY:
700206
show subpopulations
Gnomad4 AFR exome
AF:
0.00139
Gnomad4 AMR exome
AF:
0.00107
Gnomad4 ASJ exome
AF:
0.00469
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00119
Gnomad4 FIN exome
AF:
0.00149
Gnomad4 NFE exome
AF:
0.00958
Gnomad4 OTH exome
AF:
0.00499
GnomAD4 genome
AF:
0.00491
AC:
748
AN:
152332
Hom.:
8
Cov.:
33
AF XY:
0.00405
AC XY:
302
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00164
Gnomad4 AMR
AF:
0.00137
Gnomad4 ASJ
AF:
0.00490
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00104
Gnomad4 NFE
AF:
0.00879
Gnomad4 OTH
AF:
0.00520
Alfa
AF:
0.00561
Hom.:
3
Bravo
AF:
0.00481
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:18
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:6
Dec 28, 2017
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 04, 2017
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 13, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:4
Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 08, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BAP1: BP4, BS2 -

BAP1-related tumor predisposition syndrome Benign:4
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 18, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome Benign:3
Mar 13, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Mar 09, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 11, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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. -

Melanoma, uveal, susceptibility to, 2 Benign:1
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.043
DANN
Benign
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00044
dbscSNV1_RF
Benign
0.018
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149499021; hg19: chr3-52436441; COSMIC: COSV56237047; COSMIC: COSV56237047; API