rs777343359
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_198253.3(TERT):c.1142G>C(p.Arg381Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,564,628 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. R381H) has been classified as Uncertain significance.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.1142G>C | p.Arg381Pro | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.1142G>C | p.Arg381Pro | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.1221G>C | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.1221G>C | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.1142G>C | p.Arg381Pro | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.1142G>C | p.Arg381Pro | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.1142G>C | p.Arg381Pro | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.1142G>C | p.Arg381Pro | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152210Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000350 AC: 6AN: 171216Hom.: 0 AF XY: 0.0000329 AC XY: 3AN XY: 91320
GnomAD4 exome AF: 0.0000248 AC: 35AN: 1412418Hom.: 0 Cov.: 32 AF XY: 0.0000258 AC XY: 18AN XY: 697832
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152210Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6AN XY: 74356
ClinVar
Submissions by phenotype
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 381 of the TERT protein (p.Arg381Pro). This variant is present in population databases (rs777343359, gnomAD 0.005%). This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 21931702). ClinVar contains an entry for this variant (Variation ID: 410679). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 21931702). 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