3-52408496-T-G

Variant names:

• chr3-52408496-T-G
• rs1319729011
• NM_004656.4:c.233A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004656.4(BAP1):​c.233A>C​(p.Asn78Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N78D) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.98
• Publications: 17 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

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.233A>C	p.Asn78Thr	missense	Exon 4 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.233A>C	p.Asn78Thr	missense	Exon 4 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.233A>C	p.Asn78Thr	missense	Exon 4 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000296288.9	TSL:5	c.233A>C	p.Asn78Thr	missense	Exon 4 of 17	ENSP00000296288.5	F8W6N3
	BAP1	ENST00000470173.1	TSL:3	c.-5A>C		5_prime_UTR	Exon 3 of 6	ENSP00000417776.1	C9J7L9

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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 Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15290

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: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	BAP1-related tumor predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.044	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.35		Gain of sheet (P = 0.1451)
MVP		0.85
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.64
Mutation Taster		=157/143	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1319729011; hg19: chr3-52442512;