chr3-52404478-C-G

Variant names:

• chr3-52404478-C-G
• rs756443059
• NM_004656.4:c.1225G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_004656.4(BAP1):​c.1225G>C​(p.Val409Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V409M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.539
• Publications: 4 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: ClinGen, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.083230674).
• BP6: Variant 3-52404478-C-G is Benign according to our data. Variant chr3-52404478-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1053711.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1225G>C	p.Val409Leu	missense_variant	Exon 12 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1225G>C	p.Val409Leu	missense_variant	Exon 12 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.1171G>C	p.Val391Leu	missense_variant	Exon 12 of 17	5		ENSP00000296288.5
BAP1	ENST00000490804.1	n.653G>C		non_coding_transcript_exon_variant	Exon 2 of 3	2
BAP1	ENST00000469613.5	c.-3G>C		upstream_gene_variant		1		ENSP00000418320.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BAP1-related tumor predisposition syndrome Uncertain:1

Sep 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces valine with leucine at codon 409 of the BAP1 protein (p.Val409Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 28062663). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Jul 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with melanoma (O'Shea et al., 2017); This variant is associated with the following publications: (PMID: 28062663) -

Hereditary cancer-predisposing syndrome Benign:1

Apr 16, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.2
DANN	Benign	0.97
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		0.54
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.020	B;.
Vest4		0.37
MutPred		0.057		Gain of helix (P = 0.062);.;
MVP		0.48
MPC		0.40
ClinPred		0.14	T
GERP RS		3.9
PromoterAI		-0.16	Neutral
Varity_R		0.042
gMVP		0.18
Mutation Taster		=93/7	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: rs756443059; hg19: chr3-52438494; COSMIC: COSV56235470;