NM_004656.4:c.*641C>T

Variant names:

• chr3-52401647-G-A
• rs773360470
• NM_004656.4:c.*641C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004656.4(BAP1):​c.*641C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 84,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: BAP1 NM_004656.4 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.511
• 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.*641C>T		3_prime_UTR	Exon 17 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.*641C>T		3_prime_UTR	Exon 17 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.*641C>T		3_prime_UTR	Exon 17 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000469613.5	TSL:1	c.*641C>T		3_prime_UTR	Exon 5 of 5	ENSP00000418320.1	H7C4V7
	BAP1	ENST00000296288.9	TSL:5	c.*641C>T		3_prime_UTR	Exon 17 of 17	ENSP00000296288.5	F8W6N3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000236 AC: 2 AN: 84896 Hom.: 0 Cov.: 0 AF XY: 0.0000254 AC XY: 1 AN XY: 39332

⚠️ 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: 3910

American (AMR) AF: 0.00 AC: 0 AN: 3162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5140

East Asian (EAS) AF: 0.00 AC: 0 AN: 11466

South Asian (SAS) AF: 0.00 AC: 0 AN: 898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 498

European-Non Finnish (NFE) AF: 0.0000381 AC: 2 AN: 52432

Other (OTH) AF: 0.00 AC: 0 AN: 6924

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	BAP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.31
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs773360470; hg19: chr3-52435663;