NM_004656.4:c.*441G>T

Variant names:

• chr3-52401847-C-A
• rs146324979
• NM_004656.4:c.*441G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004656.4(BAP1):​c.*441G>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 0.000952 in 292,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: BAP1 NM_004656.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.270
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-52401847-C-A is Benign according to our data. Variant chr3-52401847-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 903575.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00158 (240/152296) while in subpopulation AFR AF = 0.00532 (221/41558). AF 95% confidence interval is 0.00474. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 240 AD gene.

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.*441G>T		3_prime_UTR	Exon 17 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.*441G>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.*441G>T		3_prime_UTR	Exon 17 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000478368.1	TSL:1	c.*441G>T		3_prime_UTR	Exon 5 of 5	ENSP00000420647.1	H0Y8E8
	BAP1	ENST00000469613.5	TSL:1	c.*441G>T		3_prime_UTR	Exon 5 of 5	ENSP00000418320.1	H7C4V7

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.000277 AC: 39 AN: 140630 Hom.: 0 Cov.: 0 AF XY: 0.000204 AC XY: 14 AN XY: 68780

African (AFR) AF: 0.00590 AC: 33 AN: 5592

American (AMR) AF: 0.00 AC: 0 AN: 6210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6520

East Asian (EAS) AF: 0.00 AC: 0 AN: 14608

South Asian (SAS) AF: 0.00 AC: 0 AN: 9428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 85266

Other (OTH) AF: 0.000615 AC: 6 AN: 9760

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74462

African (AFR) AF: 0.00532 AC: 221 AN: 41558

American (AMR) AF: 0.000914 AC: 14 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00201 Hom.: 1

Bravo AF: 0.00192

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	BAP1-related tumor predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.49
PhyloP100		0.27
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs146324979; hg19: chr3-52435863;