chr7-124892313-T-C
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_015450.3(POT1):c.77A>G(p.Tyr26Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000013 in 1,544,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y26N) has been classified as Uncertain significance.
Frequency
Consequence
NM_015450.3 missense
Scores
Clinical Significance
Conservation
Publications
- pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- tumor predisposition syndrome 3Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- glioma susceptibility 9Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- thyroid gland carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- cerebroretinal microangiopathy with calcifications and cysts 3Inheritance: AR Classification: LIMITED Submitted by: G2P, Ambry Genetics
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POT1 | NM_015450.3 | c.77A>G | p.Tyr26Cys | missense_variant | Exon 6 of 19 | ENST00000357628.8 | NP_056265.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151480Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 7.18e-7 AC: 1AN: 1392642Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 691558 show subpopulations
GnomAD4 genome AF: 0.00000660 AC: 1AN: 151480Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 73998 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1
- -
Tumor predisposition syndrome 3 Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 26 of the POT1 protein (p.Tyr26Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. 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: 475102). This missense change has been observed in individual(s) with clinical features of POT1-related conditions (Invitae). -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.Y26C variant (also known as c.77A>G), located in coding exon 2 of the POT1 gene, results from an A to G substitution at nucleotide position 77. The tyrosine at codon 26 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious 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