rs35448940

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004656.4(BAP1):c.1838C>T(p.Thr613Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,614,082 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T613P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 5 hom. )

Consequence

BAP1
NM_004656.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 2.24

Publications

11 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: Genomics England PanelApp, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039590895).

BP6

Variant 3-52403190-G-A is Benign according to our data. Variant chr3-52403190-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00354 (539/152268) while in subpopulation AFR AF = 0.0124 (516/41550). AF 95% confidence interval is 0.0115. There are 2 homozygotes in GnomAd4. There are 264 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 539 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004656.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	NM_004656.4	MANE Select	c.1838C>T	p.Thr613Met	missense	Exon 14 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.1784C>T	p.Thr595Met	missense	Exon 14 of 17	NP_001397701.1	F8W6N3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BAP1	ENST00000460680.6	TSL:1 MANE Select	c.1838C>T	p.Thr613Met	missense	Exon 14 of 17	ENSP00000417132.1	Q92560
BAP1	ENST00000478368.1	TSL:1	c.341C>T	p.Thr114Met	missense	Exon 2 of 5	ENSP00000420647.1	H0Y8E8
BAP1	ENST00000469613.5	TSL:1	c.118-349C>T		intron	N/A	ENSP00000418320.1	H7C4V7

Frequencies

GnomAD3 genomes

AF:

0.00350

AC:

533

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000923

AC:

232

AN:

251422

AF XY:

0.000699

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000410

AC:

599

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

270

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0137

AC:

460

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1112012

Other (OTH)

AF:

0.00121

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00354

AC:

539

AN:

152268

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

264

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0124

AC:

516

AN:

41550

American (AMR)

AF:

0.000981

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00220

Hom.:

Bravo

AF:

0.00419

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00117

AC:

142

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

BAP1-related tumor predisposition syndrome (4)

not specified (5)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Melanoma, uveal, susceptibility to, 2 (1)

Melanoma, uveal, susceptibility to, 2;C3280492:BAP1-related tumor predisposition syndrome;C5676925:Kury-Isidor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.021

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

2.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.34

REVEL

Benign

0.055

Sift

Benign

0.063

Sift4G

Benign

0.17

Polyphen

0.0010

Vest4

0.19

MVP

0.59

MPC

0.40

ClinPred

0.0017

GERP RS

3.6

PromoterAI

0.0076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.21

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over