rs868339867

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1PM2PM5PP3_ModeratePP5

The NM_004656.4(BAP1):c.606G>T(p.Trp202Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W202R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BAP1
NM_004656.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.87

Publications

2 publications found

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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS1

Transcript NM_004656.4 (BAP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2450417

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-52406884-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1399300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 3-52406882-C-A is Pathogenic according to our data. Variant chr3-52406882-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 485293.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4 link	c.606G>T	p.Trp202Cys	missense_variant	Exon 8 of 17	ENST00000460680.6	NP_004647.1	Q92560A0A024R305

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BAP1	ENST00000460680.6 link	c.606G>T	p.Trp202Cys	missense_variant	Exon 8 of 17	1	NM_004656.4	ENSP00000417132.1	Q92560
BAP1	ENST00000296288.9 link	c.606G>T	p.Trp202Cys	missense_variant	Exon 8 of 17	5		ENSP00000296288.5	F8W6N3
BAP1	ENST00000471532.5 link	n.321G>T		non_coding_transcript_exon_variant	Exon 4 of 5	5
BAP1	ENST00000483984.5 link	n.463G>T		non_coding_transcript_exon_variant	Exon 7 of 7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701586

African (AFR)

AF:

0.00

AC:

AN:

32488

American (AMR)

AF:

0.00

AC:

AN:

38636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25406

East Asian (EAS)

AF:

0.00

AC:

AN:

37324

South Asian (SAS)

AF:

0.00

AC:

AN:

80812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50422

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089186

Other (OTH)

AF:

0.00

AC:

AN:

58748

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 06, 2022

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W202C variant (also known as c.606G>T), located in coding exon 8 of the BAP1 gene, results from a G to T substitution at nucleotide position 606. The tryptophan at codon 202 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid change has been observed in multiple individuals with a personal and/or family history that is consistent with BAP1-related disease (Ambry internal data; Personal communication; De Rienzo A et al. Cancer Res. 2016 Jan;76(2):319-28). A close match alteration at this same codon (c.604T>C, p.W202R) has been observed in a family with BAP1-associated phenotype (Kittaneh M et al. J Transl Med 2018 Jul;16(1):194). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

BAP1-related tumor predisposition syndrome

Uncertain:1

Mar 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts the p.Trp202 amino acid residue in BAP1. Other variant(s) that disrupt this residue have been observed in individuals with BAP1-related conditions (PMID: 30001711), which suggests that this may be a clinically significant amino acid residue. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces tryptophan with cysteine at codon 202 of the BAP1 protein (p.Trp202Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with BAP1-related conditions (PMID: 26554828, Invitae). ClinVar contains an entry for this variant (Variation ID: 485293). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

4.0

H;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-13

D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.74

Loss of catalytic residue at W202 (P = 0.038);Loss of catalytic residue at W202 (P = 0.038);

MVP

0.83

MPC

3.2

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

1.0

Mutation Taster

=11/89

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over