rs199422305
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_198253.3(TERT):c.2935C>T(p.Arg979Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,826 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R979Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2935C>T | p.Arg979Trp | missense_variant | 12/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2746C>T | p.Arg916Trp | missense_variant | 11/15 | ||
TERT | NR_149162.3 | n.2643C>T | non_coding_transcript_exon_variant | 9/13 | |||
TERT | NR_149163.3 | n.2607C>T | non_coding_transcript_exon_variant | 9/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2935C>T | p.Arg979Trp | missense_variant | 12/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461826Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | - - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects TERT function (PMID: 12167716, 21602826, 23901009, 28154186). 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. ClinVar contains an entry for this variant (Variation ID: 39118). This missense change has been observed in individual(s) with with dyskeratosis congenita and pulmonary fibrosis, as well as in an individual with agranulocytosis and aplastic anemia (PMID: 15885610, 26360549). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 979 of the TERT protein (p.Arg979Trp). - |
Aplastic anemia Other:1
not provided, no classification provided | literature only | Radiation Cancer Biology Lab, University of Rajasthan Jaipur | - | - - |
Dyskeratosis congenita, autosomal dominant 1 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