rs199422298
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_198253.3(TERT):c.2147C>T(p.Ala716Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A716T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2147C>T | p.Ala716Val | missense_variant | 6/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2147C>T | p.Ala716Val | missense_variant | 6/15 | ||
TERT | NR_149162.3 | n.2226C>T | non_coding_transcript_exon_variant | 6/13 | |||
TERT | NR_149163.3 | n.2210-20C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2147C>T | p.Ala716Val | missense_variant | 6/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461756Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727164
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2020 | Published functional studies demonstrate a damaging effect: reduced telomerase activity and telomere length (Du 2009, Vulliamy 2011); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29596117, 18931339, 21931702, 23618685, 29146883, 20301779, 23538340) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 716 of the TERT protein (p.Ala716Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TERT-related conditions (PMID: 18931339, 21931702, 29146883; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39109). 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 expected to disrupt TERT protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 18931339, 21931702). This variant disrupts the p.Ala716 amino acid residue in TERT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30203795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2017 | The p.A716V variant (also known as c.2147C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2147. The alanine at codon 716 is replaced by valine, an amino acid with similar properties. This variant was previously identified in a child with severe pancytopenia and a significant family history of aplastic anemia and lung disease; the p.A716V variant showed a significant reduction in telomerase activity (14% of wild type), and telomere length was determined to be below the 1st percentile of normal controls for this patient (Du HY et al. Blood., 2009 Jan;113(2):309-16). In our internal cohort, this variant was detected in an individual with aplastic anemia, pulmonary fibrosis, and exudative retinopathy. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Aplastic anemia Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at