NM_004656.4:c.*300A>G

Variant names:

• chr3-52401988-T-C
• rs150842955
• NM_004656.4:c.*300A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_004656.4(BAP1):​c.*300A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 539,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BAP1 NM_004656.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• 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, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-52401988-T-C is Benign according to our data. Variant chr3-52401988-T-C is described in ClinVar as Benign. ClinVar VariationId is 903579.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00139 (211/152316) while in subpopulation AFR AF = 0.00488 (203/41568). AF 95% confidence interval is 0.00433. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 211 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.*300A>G		3_prime_UTR	Exon 17 of 17	NP_004647.1	Q92560
	BAP1	NM_001410772.1		c.*300A>G		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.*300A>G		3_prime_UTR	Exon 17 of 17	ENSP00000417132.1	Q92560
	BAP1	ENST00000478368.1	TSL:1	c.*300A>G		3_prime_UTR	Exon 5 of 5	ENSP00000420647.1	H0Y8E8
	BAP1	ENST00000469613.5	TSL:1	c.*300A>G		3_prime_UTR	Exon 5 of 5	ENSP00000418320.1	H7C4V7

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000181 AC: 70 AN: 387518 Hom.: 0 Cov.: 3 AF XY: 0.000174 AC XY: 35 AN XY: 201126

African (AFR) AF: 0.00534 AC: 62 AN: 11604

American (AMR) AF: 0.00 AC: 0 AN: 15652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12430

East Asian (EAS) AF: 0.0000369 AC: 1 AN: 27120

South Asian (SAS) AF: 0.00 AC: 0 AN: 39240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1712

European-Non Finnish (NFE) AF: 0.00000430 AC: 1 AN: 232682

Other (OTH) AF: 0.000261 AC: 6 AN: 23008

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74482

African (AFR) AF: 0.00488 AC: 203 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.00147

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.45
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		0.0
PromoterAI		-0.012	Neutral

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: rs150842955; hg19: chr3-52436004;