rs750497661
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_198253.3(TERT):c.670C>T(p.Arg224Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R224G) has been classified as Uncertain significance.
Frequency
Consequence
NM_198253.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.670C>T | p.Arg224Cys | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.670C>T | p.Arg224Cys | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.749C>T | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.749C>T | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.670C>T | p.Arg224Cys | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.670C>T | p.Arg224Cys | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.670C>T | p.Arg224Cys | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.670C>T | p.Arg224Cys | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 exomes AF: 0.00000521 AC: 1AN: 191896Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 107570
GnomAD4 exome AF: 6.99e-7 AC: 1AN: 1431266Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 711102
GnomAD4 genome ? Cov.: 34
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 07, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 224 of the TERT protein (p.Arg224Cys). 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 variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 581289). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2022 | The p.R224C variant (also known as c.670C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 670. The arginine at codon 224 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at