rs79014342

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S596T) has been classified as Likely pathogenic.

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:15O:1

Conservation

PhyloP100: 0.0150

Publications

13 publications found

Variant links:

COSMIC-nc: COSV56232053

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 Gene-Disease associations (from GenCC):

BAP1-related tumor predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Kury-Isidor syndrome
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
renal cell carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

BAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-52403241-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 800323.Status of the report is no_assertion_criteria_provided, 0 stars.

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 VariationId is 133664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
BAP1	NM_004656.4 link	c.1786A>G	p.Ser596Gly	missense_variant	Exon 14 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6 link	c.1786A>G	p.Ser596Gly	missense_variant	Exon 14 of 17	1	NM_004656.4	ENSP00000417132.1

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

GnomAD2 exomes

AF:

0.00595

AC:

1497

AN:

251410

AF XY:

0.00457

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 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

African (AFR)

AF:

0.0786

AC:

2632

AN:

33480

American (AMR)

AF:

0.00631

AC:

282

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000397

AC:

442

AN:

1112006

Other (OTH)

AF:

0.00623

AC:

376

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

258

517

775

1034

1292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0220

AC:

3346

AN:

152328

Hom.:

126

Cov.:

AF XY:

0.0210

AC XY:

1564

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0750

AC:

3118

AN:

41554

American (AMR)

AF:

0.00895

AC:

137

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000617

AC:

AN:

68034

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00813

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:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BAP1-related tumor predisposition syndrome

Benign:5

Mar 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2024

Myriad Genetics, Inc.

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4Other:1

Apr 12, 2016

GeneDx

Significance: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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Apr 12, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Feb 06, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 18, 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. -

Mar 23, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.4

(source)

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;.;.

PhyloP100

0.015

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

PromoterAI

-0.0086

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.023

gMVP

0.28

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over