rs1553646284

Variant names:

• chr3-52409558-G-A
• rs1553646284
• NM_004656.4:c.118C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-52409558-G-A
• chr3-52409558-G-C
• chr3-52409558-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.118C>T​(p.Gln40*) variant causes a stop gained 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAP1 NM_004656.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.73
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52409558-G-A is Pathogenic according to our data. Variant chr3-52409558-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 539912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.118C>T	p.Gln40*	stop_gained	Exon 3 of 17	NP_004647.1
	BAP1	NM_001410772.1		c.118C>T	p.Gln40*	stop_gained	Exon 3 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.118C>T	p.Gln40*	stop_gained	Exon 3 of 17	ENSP00000417132.1
	BAP1	ENST00000296288.9	TSL:5	c.118C>T	p.Gln40*	stop_gained	Exon 3 of 17	ENSP00000296288.5
	BAP1	ENST00000470173.1	TSL:3	c.-120C>T		5_prime_UTR	Exon 2 of 6	ENSP00000417776.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.7
Vest4		0.94
GERP RS		5.0
PromoterAI		0.034	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1553646284; hg19: chr3-52443574; COSMIC: COSV56230759; COSMIC: COSV56230759;