chr5-1279416-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_198253.3(TERT):c.2005C>T(p.Arg669Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,551,682 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. R669L) 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 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2005C>T | p.Arg669Trp | missense_variant | 5/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2005C>T | p.Arg669Trp | missense_variant | 5/15 | ||
TERT | NR_149162.3 | n.2084C>T | non_coding_transcript_exon_variant | 5/13 | |||
TERT | NR_149163.3 | n.2084C>T | non_coding_transcript_exon_variant | 5/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2005C>T | p.Arg669Trp | missense_variant | 5/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000195 AC: 3AN: 154146Hom.: 0 AF XY: 0.0000242 AC XY: 2AN XY: 82684
GnomAD4 exome AF: 0.0000114 AC: 16AN: 1399520Hom.: 0 Cov.: 33 AF XY: 0.0000130 AC XY: 9AN XY: 690676
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 09, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 669 of the TERT protein (p.Arg669Trp). 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. This missense change has been observed in individual(s) with pulmonary fibrosis (PMID: 32315675). ClinVar contains an entry for this variant (Variation ID: 539196). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at