chr3-52403733-G-A

Variant names:

• chr3-52403733-G-A
• rs749456076
• NM_004656.4:c.1412C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_004656.4(BAP1):​c.1412C>T​(p.Ala471Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A471T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.16
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-52403733-G-A is Benign according to our data. Variant chr3-52403733-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472668.

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.1412C>T	p.Ala471Val	missense	Exon 13 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.1358C>T	p.Ala453Val	missense	Exon 13 of 17	NP_001397701.1	F8W6N3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	ENST00000460680.6	TSL:1 MANE Select	c.1412C>T	p.Ala471Val	missense	Exon 13 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000469613.5	TSL:1	c.117+68C>T		intron	N/A	ENSP00000418320.1	H7C4V7
	BAP1	ENST00000296288.9	TSL:5	c.1358C>T	p.Ala453Val	missense	Exon 13 of 17	ENSP00000296288.5	F8W6N3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	BAP1-related tumor predisposition syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0044	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.29	T
Polyphen		0.69	P
Vest4		0.60
MutPred		0.13		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.77
MPC		0.48
ClinPred		0.54	D
GERP RS		6.0
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.070
gMVP		0.43
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs749456076; hg19: chr3-52437749;