rs753638532
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_015450.3(POT1):c.703G>A(p.Val235Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,557,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V235A) has been classified as Uncertain significance.
Frequency
Consequence
NM_015450.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.703G>A | p.Val235Ile | missense_variant, splice_region_variant | 10/19 | ENST00000357628.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POT1 | ENST00000357628.8 | c.703G>A | p.Val235Ile | missense_variant, splice_region_variant | 10/19 | 2 | NM_015450.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151980Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000179 AC: 4AN: 224012Hom.: 0 AF XY: 0.0000247 AC XY: 3AN XY: 121492
GnomAD4 exome AF: 0.00000783 AC: 11AN: 1405314Hom.: 0 Cov.: 28 AF XY: 0.00000715 AC XY: 5AN XY: 699516
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 151980Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74242
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 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; Observed in an individual with AML (Lim et al., 2021); This variant is associated with the following publications: (PMID: 34193977, 28393830) - |
Tumor predisposition syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 235 of the POT1 protein (p.Val235Ile). This variant is present in population databases (rs753638532, gnomAD 0.02%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 34193977). ClinVar contains an entry for this variant (Variation ID: 486137). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2022 | The p.V235I variant (also known as c.703G>A) is located in coding exon 6 of the POT1 gene. The valine at codon 235 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This variant was described as a germline finding in 1/3323 consecutive patients who had clinical testing for variants associated with hematologic malignancies (Lim TL et al. Leukemia, 2022 01;36:283-287). This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other 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