rs1553645806
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004656.4(BAP1):c.517_518insT(p.Tyr173LeufsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y173Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004656.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.517_518insT | p.Tyr173LeufsTer10 | frameshift_variant | 7/17 | ENST00000460680.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.517_518insT | p.Tyr173LeufsTer10 | frameshift_variant | 7/17 | 1 | NM_004656.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
BAP1-related tumor predisposition syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 06, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 24, 2019 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant has not been reported in the literature in individuals with BAP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr173Leufs*10) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 01, 2024 | The c.517dupT pathogenic mutation, located in coding exon 7 of the BAP1 gene, results from a duplication of T at nucleotide position 517, causing a translational frameshift with a predicted alternate stop codon (p.Y173Lfs*10). This mutation, also designated as c.517insT in published literature, has been reported in individuals with personal and family histories of BAP1-related tumors, including a peritoneal malignant mesothelioma demonstrating BAP1 protein loss by IHC (Panou V et al. J Clin Oncol, 2018 10;36:2863-2871; Walpole S et al. J Natl Cancer Inst, 2018 12;110:1328-1341). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at