rs758341603
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_015450.3(POT1):c.1294C>T(p.Arg432Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015450.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1294C>T | p.Arg432Ter | stop_gained | 14/19 | ENST00000357628.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POT1 | ENST00000357628.8 | c.1294C>T | p.Arg432Ter | stop_gained | 14/19 | 2 | NM_015450.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460214Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4AN XY: 726496
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Tumor predisposition syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Arg432*) in the POT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570). This variant is present in population databases (rs758341603, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with sarcoma (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 541876). 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. - |
Hoyeraal-Hreidarsson syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Bone Marrow Failure laboratory, Queen Mary University London | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at