rs869312757
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004656.4(BAP1):c.1063C>T(p.Gln355*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004656.4 stop_gained
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BAP1 | NM_004656.4 | c.1063C>T | p.Gln355* | stop_gained | Exon 11 of 17 | ENST00000460680.6 | NP_004647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BAP1 | ENST00000460680.6 | c.1063C>T | p.Gln355* | stop_gained | Exon 11 of 17 | 1 | NM_004656.4 | ENSP00000417132.1 | ||
BAP1 | ENST00000296288.9 | c.1009C>T | p.Gln337* | stop_gained | Exon 11 of 17 | 5 | ENSP00000296288.5 | |||
BAP1 | ENST00000490804.1 | n.491C>T | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
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The p.Q355* pathogenic mutation (also known as c.1063C>T), located in coding exon 11 of the BAP1 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This mutation was observed in a patient with a history of melanoma and kidney cancer who underwent multi-gene panel testing (Shirts BH et al. Genet. Med., 2016 Oct;18:974-81). 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. -
BAP1-related tumor predisposition syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gln355*) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with melanoma and kidney cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224520). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at