7-124835303-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_015450.3(POT1):c.1481T>A(p.Ile494Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,772 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 Uncertain significance (★★).
Frequency
Consequence
NM_015450.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1481T>A | p.Ile494Lys | missense_variant | Exon 15 of 19 | ENST00000357628.8 | NP_056265.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251288Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461772Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727190
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Long telomere syndrome Pathogenic:1
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Tumor predisposition syndrome 3 Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 494 of the POT1 protein (p.Ile494Lys). This variant is present in population databases (rs774858551, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 475046). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POT1 protein function with a negative predictive value of 80%. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.I494K variant (also known as c.1481T>A), located in coding exon 11 of the POT1 gene, results from a T to A substitution at nucleotide position 1481. The isoleucine at codon 494 is replaced by lysine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at