NM_004656.4:c.255+136C>T

Variant names:

• chr3-52408338-G-A
• rs123602
• NM_004656.4:c.255+136C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004656.4(BAP1):​c.255+136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,260,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BAP1 NM_004656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.915
• Publications: 9 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.255+136C>T		intron_variant	Intron 4 of 16	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.255+136C>T		intron_variant	Intron 4 of 16	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000119 AC: 15 AN: 1260034 Hom.: 0 AF XY: 0.0000127 AC XY: 8 AN XY: 627620

African (AFR) AF: 0.00 AC: 0 AN: 28584

American (AMR) AF: 0.0000282 AC: 1 AN: 35520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24236

East Asian (EAS) AF: 0.00 AC: 0 AN: 35074

South Asian (SAS) AF: 0.00 AC: 0 AN: 75476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3920

European-Non Finnish (NFE) AF: 0.0000136 AC: 13 AN: 955852

Other (OTH) AF: 0.0000187 AC: 1 AN: 53406

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 59

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.92
PhyloP100		-0.92

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: rs123602; hg19: chr3-52442354;