rs764303246
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_015450.3(POT1):c.1482A>G(p.Ile494Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I494K) has been classified 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1482A>G | p.Ile494Met | missense_variant | 15/19 | ENST00000357628.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POT1 | ENST00000357628.8 | c.1482A>G | p.Ile494Met | missense_variant | 15/19 | 2 | NM_015450.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251290Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135828
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461778Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727200
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
POT1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 12, 2022 | The POT1 c.1482A>G variant is predicted to result in the amino acid substitution p.Ile494Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-124475356-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28393830) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2023 | The p.I494M variant (also known as c.1482A>G), located in coding exon 11 of the POT1 gene, results from an A to G substitution at nucleotide position 1482. The isoleucine at codon 494 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Tumor predisposition syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 494 of the POT1 protein (p.Ile494Met). This variant is present in population databases (rs764303246, gnomAD 0.007%). 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: 576671). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at