rs773947541

Positions:

chr3-52403892-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_004656.4(BAP1):c.1253A>G(p.Tyr418Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

BAP1
NM_004656.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.21

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:

BAP1 (HGNC:):

BAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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). GenCC has associacion of gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.

BS2

High AC in GnomAdExome4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4 linkuse as main transcript	c.1253A>G	p.Tyr418Cys	missense_variant, splice_region_variant	13/17	ENST00000460680.6	NP_004647.1	Q92560A0A024R305

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BAP1	ENST00000460680.6 linkuse as main transcript	c.1253A>G	p.Tyr418Cys	missense_variant, splice_region_variant	13/17	1	NM_004656.4	ENSP00000417132.1	Q92560
BAP1	ENST00000469613.5 linkuse as main transcript	c.26A>G	p.Tyr9Cys	missense_variant, splice_region_variant	2/5	1		ENSP00000418320.1	H7C4V7
BAP1	ENST00000296288.9 linkuse as main transcript	c.1199A>G	p.Tyr400Cys	missense_variant, splice_region_variant	13/17	5		ENSP00000296288.5	F8W6N3
BAP1	ENST00000490804.1 linkuse as main transcript	n.681A>G		splice_region_variant, non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251194

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

BAP1-related tumor predisposition syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 418 of the BAP1 protein (p.Tyr418Cys). This variant is present in population databases (rs773947541, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma (PMID: 28062663). ClinVar contains an entry for this variant (Variation ID: 569477). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 16, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2023	The p.Y418C variant (also known as c.1253A>G), located in coding exon 13 of the BAP1 gene, results from an A to G substitution at nucleotide position 1253. The tyrosine at codon 418 is replaced by cysteine, an amino acid with highly dissimilar properties. One study identified this alteration in 1/1977 melanoma patients and 0/754 controls (O'Shea SJ et al. Hum. Mol. Genet., 2017 02;26:717-728). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2024	This missense variant replaces tyrosine with cysteine at codon 418 of the BAP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant has no significant impact in deubiquitinase assays (PMID: 28062663). This variant has been reported in individuals affected with melanoma (PMID: 28062663). This variant has been identified in 3/251194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with melanoma (O'Shea et al., 2017); This variant is associated with the following publications: (PMID: 28062663) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.0029

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.038

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.15

T;T

Polyphen

0.93

P;.

Vest4

0.71

MutPred

0.26

Gain of methylation at K419 (P = 0.0134);.;

MVP

0.80

MPC

0.97

ClinPred

0.36

GERP RS

6.0

Varity_R

0.13

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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