chr3-52406839-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4BP6BS2_Supporting

The NM_004656.4(BAP1):c.649G>A(p.Ala217Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000706 in 1,557,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A217A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

BAP1
NM_004656.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.87

Publications

0 publications found

Variant links:

COSMIC-nc: COSV56242533

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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38337877).

BP6

Variant 3-52406839-C-T is Benign according to our data. Variant chr3-52406839-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472711.

BS2

High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4 link	c.649G>A	p.Ala217Thr	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.649G>A	p.Ala217Thr	missense_variant	Exon 8 of 17	1	NM_004656.4	ENSP00000417132.1	Q92560
BAP1	ENST00000296288.9 link	c.649G>A	p.Ala217Thr	missense_variant	Exon 8 of 17	5		ENSP00000296288.5	F8W6N3
BAP1	ENST00000471532.5 link	n.364G>A		non_coding_transcript_exon_variant	Exon 4 of 5	5
BAP1	ENST00000483984.5 link	n.506G>A		non_coding_transcript_exon_variant	Exon 7 of 7	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

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

GnomAD4 exome

AF:

0.00000641

AC:

AN:

1404826

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

693518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31958

American (AMR)

AF:

0.00

AC:

AN:

36478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25218

East Asian (EAS)

AF:

0.00

AC:

AN:

36270

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000739

AC:

AN:

1081840

Other (OTH)

AF:

0.00

AC:

AN:

58230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BAP1-related tumor predisposition syndrome

Uncertain:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 217 of the BAP1 protein (p.Ala217Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAP1 protein function with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 30, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A217T variant (also known as c.649G>A), located in coding exon 8 of the BAP1 gene, results from a G to A substitution at nucleotide position 649. The alanine at codon 217 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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. -

BAP1-related disorder

Uncertain:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BAP1 c.649G>A variant is predicted to result in the amino acid substitution p.Ala217Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted with uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/472711/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.21

Sift

Benign

0.086

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.95

P;.

Vest4

0.49

MutPred

0.53

Gain of glycosylation at T218 (P = 0.1055);Gain of glycosylation at T218 (P = 0.1055);

MVP

0.66

MPC

2.1

ClinPred

0.82

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.84

Mutation Taster

=37/63

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over