NM_004656.4:c.1729+8T>C

Variant names:

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.1729+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,613,504 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 52 hom. )

Consequence

BAP1
NM_004656.4 splice_region, intron

Scores

Splicing: ADA: 0.0001674

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: -0.160

Publications

4 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 (BayesDel_noAF=-0.81).

BP6

Variant 3-52403408-A-G is Benign according to our data. Variant chr3-52403408-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00363 (553/152300) while in subpopulation NFE AF = 0.00671 (456/68004). AF 95% confidence interval is 0.0062. There are 2 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 553 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.1729+8T>C		splice_region intron	N/A	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.1675+8T>C		splice_region intron	N/A	NP_001397701.1	F8W6N3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BAP1	ENST00000460680.6	TSL:1 MANE Select	c.1729+8T>C	splice_region intron	N/A	ENSP00000417132.1	Q92560
BAP1	ENST00000478368.1	TSL:1	c.232+8T>C	splice_region intron	N/A	ENSP00000420647.1	H0Y8E8
BAP1	ENST00000469613.5	TSL:1	c.117+393T>C	intron	N/A	ENSP00000418320.1	H7C4V7

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00670

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00347

AC:

868

AN:

250326

AF XY:

0.00375

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.000697

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000704

Gnomad NFE exome

AF:

0.00601

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00654

AC:

9554

AN:

1461204

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

4721

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33472

American (AMR)

AF:

0.000850

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000804

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00336

AC:

290

AN:

86256

European-Finnish (FIN)

AF:

0.000643

AC:

AN:

52904

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00795

AC:

8836

AN:

1111870

Other (OTH)

AF:

0.00484

AC:

292

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

630

1261

1891

2522

3152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.00363

AC:

553

AN:

152300

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41558

American (AMR)

AF:

0.00131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00671

AC:

456

AN:

68004

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

121

151

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:

0.00466

Hom.:

Bravo

AF:

0.00338

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00658

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (5)

BAP1-related tumor predisposition syndrome (4)

Hereditary cancer-predisposing syndrome (3)

BAP1-related tumor predisposition syndrome;C5676925:Kury-Isidor syndrome (1)

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

(source)

DANN

Benign

0.77

PhyloP100

-0.16

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over