3-52408338-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004656.4(BAP1):​c.255+136C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,410,818 control chromosomes in the GnomAD database, including 22,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2900 hom., cov: 32)
  • Exomes 𝑓: 0.17 (19418 hom.)
• Consequence: BAP1 NM_004656.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-52408338-G-C is Benign according to our data. Variant chr3-52408338-G-C is described in ClinVar as Benign. ClinVar VariationId is 1252465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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.255+136C>G		intron	N/A	NP_004647.1
	BAP1	NM_001410772.1		c.255+136C>G		intron	N/A	NP_001397701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAP1	ENST00000460680.6	TSL:1 MANE Select	c.255+136C>G		intron	N/A	ENSP00000417132.1
	BAP1	ENST00000296288.9	TSL:5	c.255+136C>G		intron	N/A	ENSP00000296288.5
	BAP1	ENST00000470173.1	TSL:3	c.18+136C>G		intron	N/A	ENSP00000417776.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27985 AN: 151984 Hom.: 2898 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.170 AC: 213842 AN: 1258716 Hom.: 19418 AF XY: 0.168 AC XY: 105219 AN XY: 627024

African (AFR) AF: 0.275 AC: 7857 AN: 28544

American (AMR) AF: 0.126 AC: 4463 AN: 35516

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3688 AN: 24230

East Asian (EAS) AF: 0.0245 AC: 860 AN: 35072

South Asian (SAS) AF: 0.118 AC: 8909 AN: 75452

European-Finnish (FIN) AF: 0.0935 AC: 4486 AN: 47960

Middle Eastern (MID) AF: 0.158 AC: 619 AN: 3918

European-Non Finnish (NFE) AF: 0.182 AC: 173641 AN: 954660

Other (OTH) AF: 0.175 AC: 9319 AN: 53364

GnomAD4 genome AF: 0.184 AC: 28004 AN: 152102 Hom.: 2900 Cov.: 32 AF XY: 0.177 AC XY: 13185 AN XY: 74368

African (AFR) AF: 0.265 AC: 10983 AN: 41468

American (AMR) AF: 0.152 AC: 2315 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 549 AN: 3472

East Asian (EAS) AF: 0.0299 AC: 155 AN: 5190

South Asian (SAS) AF: 0.111 AC: 536 AN: 4822

European-Finnish (FIN) AF: 0.0839 AC: 889 AN: 10592

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11960 AN: 67974

Other (OTH) AF: 0.198 AC: 418 AN: 2106

Alfa AF: 0.0535 Hom.: 59

Bravo AF: 0.192

Asia WGS AF: 0.0930 AC: 324 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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;