dbSNP rs28997577: BAP1:p.Leu334Leu (chr3-52405224-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004656.4(BAP1):c.1002A>G(p.Leu334Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,614,056 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 66 hom. )

Consequence

BAP1
NM_004656.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.128

Publications

15 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 3-52405224-T-C is Benign according to our data. Variant chr3-52405224-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.128 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00386 (588/152274) while in subpopulation SAS AF = 0.0234 (113/4824). AF 95% confidence interval is 0.0199. There are 4 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 588 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.1002A>G	p.Leu334Leu	synonymous	Exon 11 of 17	NP_004647.1
	BAP1	NM_001410772.1		c.948A>G	p.Leu316Leu	synonymous	Exon 11 of 17	NP_001397701.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BAP1	ENST00000460680.6	TSL:1 MANE Select	c.1002A>G	p.Leu334Leu	synonymous	Exon 11 of 17	ENSP00000417132.1
BAP1	ENST00000296288.9	TSL:5	c.948A>G	p.Leu316Leu	synonymous	Exon 11 of 17	ENSP00000296288.5
BAP1	ENST00000490804.1	TSL:2	n.430A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

589

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00771

Gnomad SAS

AF:

0.0236

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00594

AC:

1494

AN:

251430

AF XY:

0.00697

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00783

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00417

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00586

AC:

8566

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

4638

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26136

East Asian (EAS)

AF:

0.00796

AC:

316

AN:

39700

South Asian (SAS)

AF:

0.0233

AC:

2008

AN:

86258

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00506

AC:

5630

AN:

1112002

Other (OTH)

AF:

0.00560

AC:

338

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

529

1058

1586

2115

2644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00386

AC:

588

AN:

152274

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41562

American (AMR)

AF:

0.00314

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0234

AC:

113

AN:

4824

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00473

AC:

322

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00369

Hom.:

Bravo

AF:

0.00306

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00498

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

BAP1-related tumor predisposition syndrome (5)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Melanoma, uveal, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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