3-52401844-G-A

Variant names:

• chr3-52401844-G-A
• rs123598
• NM_004656.4:c.*444C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004656.4(BAP1):​c.*444C>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 0.0381 in 292,396 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (143 hom., cov: 33)
  • Exomes 𝑓: 0.040 (141 hom.)
• Consequence: BAP1 NM_004656.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.271
• Publications: 15 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, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Kury-Isidor syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• 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=-0.82).
• BP6: Variant 3-52401844-G-A is Benign according to our data. Variant chr3-52401844-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 346111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0361 (5493/152308) while in subpopulation NFE AF = 0.0497 (3377/68012). AF 95% confidence interval is 0.0483. There are 143 homozygotes in GnomAd4. There are 2529 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5493 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.*444C>T		3_prime_UTR	Exon 17 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.*444C>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.*444C>T		3_prime_UTR	Exon 17 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000478368.1	TSL:1	c.*444C>T		3_prime_UTR	Exon 5 of 5	ENSP00000420647.1	H0Y8E8
	BAP1	ENST00000469613.5	TSL:1	c.*444C>T		3_prime_UTR	Exon 5 of 5	ENSP00000418320.1	H7C4V7

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5492 AN: 152190 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0421

GnomAD4 exome AF: 0.0402 AC: 5638 AN: 140088 Hom.: 141 Cov.: 0 AF XY: 0.0396 AC XY: 2709 AN XY: 68426

African (AFR) AF: 0.0150 AC: 85 AN: 5648

American (AMR) AF: 0.0435 AC: 271 AN: 6228

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 202 AN: 6514

East Asian (EAS) AF: 0.0150 AC: 220 AN: 14626

South Asian (SAS) AF: 0.0157 AC: 150 AN: 9556

European-Finnish (FIN) AF: 0.0261 AC: 65 AN: 2490

Middle Eastern (MID) AF: 0.0277 AC: 19 AN: 686

European-Non Finnish (NFE) AF: 0.0489 AC: 4135 AN: 84606

Other (OTH) AF: 0.0504 AC: 491 AN: 9734

GnomAD4 genome AF: 0.0361 AC: 5493 AN: 152308 Hom.: 143 Cov.: 33 AF XY: 0.0340 AC XY: 2529 AN XY: 74482

African (AFR) AF: 0.0138 AC: 575 AN: 41564

American (AMR) AF: 0.0470 AC: 719 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3472

East Asian (EAS) AF: 0.0214 AC: 111 AN: 5184

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4826

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0497 AC: 3377 AN: 68012

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

Alfa AF: 0.0477 Hom.: 252

Bravo AF: 0.0371

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BAP1-related tumor predisposition syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.80
DANN	Benign	0.27
PhyloP100		-0.27
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs123598; hg19: chr3-52435860;