rs1193212091

Variant names:

• chr3-52406900-C-A
• rs1193212091
• NM_004656.4:c.588G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52406900-C-A
• chr3-52406900-C-G
• chr3-52406900-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004656.4(BAP1):​c.588G>T​(p.Trp196Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,272 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W196G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.87
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 25 uncertain in NM_004656.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	NM_004656.4	MANE Select	c.588G>T	p.Trp196Cys	missense	Exon 8 of 17	NP_004647.1
	BAP1	NM_001410772.1		c.588G>T	p.Trp196Cys	missense	Exon 8 of 17	NP_001397701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	ENST00000460680.6	TSL:1 MANE Select	c.588G>T	p.Trp196Cys	missense	Exon 8 of 17	ENSP00000417132.1
	BAP1	ENST00000296288.9	TSL:5	c.588G>T	p.Trp196Cys	missense	Exon 8 of 17	ENSP00000296288.5
	BAP1	ENST00000471532.5	TSL:5	n.303G>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419272 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 701848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32500

American (AMR) AF: 0.00 AC: 0 AN: 38606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.00 AC: 0 AN: 80936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089446

Other (OTH) AF: 0.00 AC: 0 AN: 58782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.12	N
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-10	D
REVEL	Uncertain	0.44
Sift	Benign	0.21	T
Sift4G	Benign	0.16	T
Polyphen		0.88	P
Vest4		0.79
MutPred		0.59		Gain of catalytic residue at P195 (P = 0.0103)
MVP		0.70
MPC		3.0
ClinPred		0.88	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.99
Mutation Taster		=11/89	disease causing

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: rs1193212091; hg19: chr3-52440916;