rs79014342

Positions:

chr3-52403242-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004656.4(BAP1):c.1786A>G(p.Ser596Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,614,170 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 126 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 124 hom. )

Consequence

BAP1
NM_004656.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.0150

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]

BAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BAP1. . Gene score misZ: 2.6442 (greater than the threshold 3.09). Trascript score misZ: 3.2667 (greater than threshold 3.09). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015929043).

BP6

Variant 3-52403242-T-C is Benign according to our data. Variant chr3-52403242-T-C is described in ClinVar as [Benign]. Clinvar id is 133664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52403242-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4 link	c.1786A>G	p.Ser596Gly	missense_variant	14/17	ENST00000460680.6	NP_004647.1	Q92560A0A024R305

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6 link	c.1786A>G	p.Ser596Gly	missense_variant	14/17	1	NM_004656.4	ENSP00000417132.1		Q92560

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3343

AN:

152210

Hom.:

126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0752

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.0206

GnomAD3 exomes

AF:

0.00595

AC:

1497

AN:

251410

Hom.:

AF XY:

0.00457

AC XY:

621

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0740

Gnomad AMR exome

AF:

0.00587

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00261

AC:

3810

AN:

1461842

Hom.:

124

Cov.:

AF XY:

0.00232

AC XY:

1686

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0786

Gnomad4 AMR exome

AF:

0.00631

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000397

Gnomad4 OTH exome

AF:

0.00623

GnomAD4 genome

AF:

0.0220

AC:

3346

AN:

152328

Hom.:

126

Cov.:

AF XY:

0.0210

AC XY:

1564

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0750

Gnomad4 AMR

AF:

0.00895

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.0247

ESP6500AA

AF:

0.0699

AC:

308

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00715

AC:

868

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

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	GeneDx	Apr 12, 2016	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	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

BAP1-related tumor predisposition syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 17, 2024	This variant is considered benign. 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

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2015	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.4

DANN

Benign

0.77

DEOGEN2

Benign

0.020

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.010

N;N;N

REVEL

Benign

0.046

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.12

MVP

0.40

MPC

0.34

ClinPred

0.00034

GERP RS

-0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.023

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over