7-124829280-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015450.3(POT1):āc.1568C>Gā(p.Ser523Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,604,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S523L) has been classified as Uncertain significance.
Frequency
Consequence
NM_015450.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.1568C>G | p.Ser523Trp | missense_variant | 16/19 | ENST00000357628.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POT1 | ENST00000357628.8 | c.1568C>G | p.Ser523Trp | missense_variant | 16/19 | 2 | NM_015450.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1452672Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 723292
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Tumor predisposition syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2022 | This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 523 of the POT1 protein (p.Ser523Trp). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 475051). This variant has not been reported in the literature in individuals affected with POT1-related conditions. This variant is not present in population databases (gnomAD no frequency). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2023 | The p.S523W variant (also known as c.1568C>G), located in coding exon 12 of the POT1 gene, results from a C to G substitution at nucleotide position 1568. The serine at codon 523 is replaced by tryptophan, an amino acid with highly dissimilar 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at