3-52407959-T-C

Variant names:

• chr3-52407959-T-C
• rs1553645926
• NM_004656.4:c.374A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_004656.4(BAP1):​c.374A>G​(p.Glu125Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E125A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-52407958-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3477532.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.374A>G	p.Glu125Gly	missense splice_region	Exon 5 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.374A>G	p.Glu125Gly	missense splice_region	Exon 5 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.374A>G	p.Glu125Gly	missense splice_region	Exon 5 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000296288.9	TSL:5	c.374A>G	p.Glu125Gly	missense splice_region	Exon 5 of 17	ENSP00000296288.5	F8W6N3
	BAP1	ENST00000470173.1	TSL:3	c.137A>G	p.Glu46Gly	missense splice_region	Exon 4 of 6	ENSP00000417776.1	C9J7L9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.45		Gain of glycosylation at Y129 (P = 0.0114)
MVP		0.87
MPC		2.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.85
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.050		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: rs1553645926; hg19: chr3-52441975;