chr7-124825302-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_015450.3(POT1):āc.1742A>Gā(p.Lys581Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K581E) has been classified as Uncertain significance.
Frequency
Consequence
NM_015450.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1742A>G | p.Lys581Arg | missense_variant | 18/19 | ENST00000357628.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POT1 | ENST00000357628.8 | c.1742A>G | p.Lys581Arg | missense_variant | 18/19 | 2 | NM_015450.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250124Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135218
GnomAD4 exome AF: 0.0000500 AC: 73AN: 1459300Hom.: 0 Cov.: 29 AF XY: 0.0000427 AC XY: 31AN XY: 725920
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74268
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2024 | The p.K581R variant (also known as c.1742A>G), located in coding exon 14 of the POT1 gene, results from an A to G substitution at nucleotide position 1742. The lysine at codon 581 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cohort of melanoma cases from CDKN2A/CDK4 negative melanoma-prone families (Potjer TP et al. Int J Cancer, 2019 05;144:2453-2464). This alteration was identified in 1 of 2928 melanoma cases and 0 of 3298 controls (Simonin-Wilmer I et al. J Med Genet, 2023 Jul;60:692-696). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. - |
Tumor predisposition syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 581 of the POT1 protein (p.Lys581Arg). This variant is present in population databases (rs201023336, gnomAD 0.006%). 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: 486134). 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