3-52407398-C-G

Variant names:

• chr3-52407398-C-G
• rs1553645838
• NM_004656.4:c.437+1G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004656.4(BAP1):​c.437+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.81
• 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: 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52407398-C-G is Pathogenic according to our data. Variant chr3-52407398-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3706351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.437+1G>C		splice_donor_variant, intron_variant	Intron 6 of 16	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.437+1G>C		splice_donor_variant, intron_variant	Intron 6 of 16	1	NM_004656.4	ENSP00000417132.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BAP1-related tumor predisposition syndrome Pathogenic:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 6 of the BAP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with BAP1-related conditions (PMID: 23684012, 28560743). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 19, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting c.437+1G>C, located in a canonic splicing site of the BAP1 is predicted to alter splicing. This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_supporting). The SpliceAI algorithm predicts that the variant impairs the splicing donor site of intron 6. To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. Based on currently available information, the variant c.437+1G>C should be considered a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		5.8
GERP RS		5.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1553645838; hg19: chr3-52441414;