3-52405878-G-C

Variant names:

• chr3-52405878-G-C
• NM_004656.4:c.818C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004656.4(BAP1):​c.818C>G​(p.Thr273Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.27

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 2.6442 (below the threshold of 3.09). Trascript score misZ: 3.2667 (above the threshold of 3.09). GenCC associations: The gene is linked to BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18849742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.818C>G	p.Thr273Ser	missense_variant	Exon 10 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.818C>G	p.Thr273Ser	missense_variant	Exon 10 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.764C>G	p.Thr255Ser	missense_variant	Exon 10 of 17	5		ENSP00000296288.5
BAP1	ENST00000471532.5	n.985C>G		non_coding_transcript_exon_variant	Exon 5 of 5	5
BAP1	ENST00000490804.1	n.-225C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.074
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.10
Sift	Benign	0.17	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0010	B;.
Vest4		0.28
MutPred		0.27		Gain of glycosylation at S276 (P = 0.0234);.;
MVP		0.65
MPC		0.34
ClinPred		0.76	D
GERP RS		5.3
Varity_R		0.079
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52439894;