rs876658018
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_198253.3(TERT):c.2575C>T(p.Arg859Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R859Q) has been classified as Likely benign.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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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.2575C>T | p.Arg859Trp | missense_variant | 9/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2575C>T | p.Arg859Trp | missense_variant | 9/15 | ||
TERT | NR_149162.3 | n.2472C>T | non_coding_transcript_exon_variant | 7/13 | |||
TERT | NR_149163.3 | n.2436C>T | non_coding_transcript_exon_variant | 7/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2575C>T | p.Arg859Trp | missense_variant | 9/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460968Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726754
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 15, 2015 | The p.Arg859Trp variant in TERT has not been previously reported in individuals with pulmonary disease or in large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though Arginine (Arg) at residue 859 is not well conserve d. In summary, the clinical significance of the p.Arg859Trp variant is uncertain . - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2023 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. ClinVar contains an entry for this variant (Variation ID: 229310). This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 859 of the TERT protein (p.Arg859Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at