rs28997577

chr3-52405224-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004656.4(BAP1):c.1002A>G(p.Leu334=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,614,056 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (66 hom.)
• Consequence: BAP1 NM_004656.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.128

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-52405224-T-C is Benign according to our data. Variant chr3-52405224-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52405224-T-C is described in Lovd as [Benign]. Variant chr3-52405224-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00386 (588/152274) while in subpopulation SAS AF= 0.0234 (113/4824). AF 95% confidence interval is 0.0199. There are 4 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 589 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAP1	NM_004656.4	c.1002A>G	p.Leu334=	synonymous_variant	11/17	ENST00000460680.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAP1	ENST00000460680.6	c.1002A>G	p.Leu334=	synonymous_variant	11/17	1	NM_004656.4	P1
BAP1	ENST00000296288.9	c.948A>G	p.Leu316=	synonymous_variant	11/17	5
BAP1	ENST00000490804.1	n.430A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 589 AN: 152156 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00594 AC: 1494 AN: 251430 Hom.: 10 AF XY: 0.00697 AC XY: 947 AN XY: 135890

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00783

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00586 AC: 8566 AN: 1461782 Hom.: 66 Cov.: 32 AF XY: 0.00638 AC XY: 4638 AN XY: 727184

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00796

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00560

GnomAD4 genome AF: 0.00386 AC: 588 AN: 152274 Hom.: 4 Cov.: 33 AF XY: 0.00402 AC XY: 299 AN XY: 74452

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00773

Gnomad4 SAS AF: 0.0234

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00341 Hom.: 2

Bravo AF: 0.00306

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 13, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

BAP1-related tumor predisposition syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2015	This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	10
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs28997577; hg19: chr3-52439240; COSMIC: COSV56231289; COSMIC: COSV56231289;