3-52401896-G-A

Variant names:

• chr3-52401896-G-A
• rs112026686
• NM_004656.4:c.*392C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004656.4(BAP1):​c.*392C>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 0.00382 in 376,600 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: BAP1 NM_004656.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.709

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006372899).
• BP6: Variant 3-52401896-G-A is Benign according to our data. Variant chr3-52401896-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 903576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00786 (1198/152360) while in subpopulation AFR AF= 0.0271 (1127/41576). AF 95% confidence interval is 0.0258. There are 16 homozygotes in gnomad4. There are 550 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.*392C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680	c.*392C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1198 AN: 152242 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00108 AC: 242 AN: 224240 Hom.: 6 Cov.: 0 AF XY: 0.000994 AC XY: 113 AN XY: 113714

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000799

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000896

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00786 AC: 1198 AN: 152360 Hom.: 16 Cov.: 33 AF XY: 0.00738 AC XY: 550 AN XY: 74498

Gnomad4 AFR AF: 0.0271

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00926

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jun 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.58
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0064	T
Vest4		0.18
MVP		0.73
GERP RS		1.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs112026686; hg19: chr3-52435912;