rs199422293
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_198253.3(TERT):c.1456C>T(p.Arg486Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,056 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486H) 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 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.1456C>T | p.Arg486Cys | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.1456C>T | p.Arg486Cys | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.1535C>T | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.1535C>T | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.1456C>T | p.Arg486Cys | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.1456C>T | p.Arg486Cys | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.1456C>T | p.Arg486Cys | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.1456C>T | p.Arg486Cys | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460056Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726300
GnomAD4 genome ? Cov.: 34
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 | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | May 19, 2022 | - - |
Dyskeratosis congenita Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 04, 2016 | The p.R486C variant (also known as c.1456C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1456. The arginine at codon 486 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in one individual with idiopathic pulmonary fibrosis. In addition, in vitro functional studies showed reduced telomerase activity and shortened telomeres (Tsakiri KD, Proc. Natl. Acad. Sci. U.S.A. 2007 May; 104(18):7552-7). This variant was previously reported in the SNPDatabase as rs199422293. This variant was not reported in population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6496 samples (12992 alleles) with coverage at this position.This amino acid position is well 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. - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2021 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 486 of the TERT protein (p.Arg486Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis (PMID: 17460043, 20502709, 27540018). ClinVar contains an entry for this variant (Variation ID: 39101). 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. 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. - |
Interstitial lung disease 2 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