rs766054124
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_198253.3(TERT):āc.724G>Cā(p.Ala242Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000949 in 1,580,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A242T) 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_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.724G>C | p.Ala242Pro | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.724G>C | p.Ala242Pro | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.803G>C | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.803G>C | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.724G>C | p.Ala242Pro | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.724G>C | p.Ala242Pro | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.724G>C | p.Ala242Pro | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.724G>C | p.Ala242Pro | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000161 AC: 3AN: 186244Hom.: 0 AF XY: 0.0000193 AC XY: 2AN XY: 103446
GnomAD4 exome AF: 0.00000770 AC: 11AN: 1428372Hom.: 0 Cov.: 35 AF XY: 0.00000564 AC XY: 4AN XY: 708894
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 242 of the TERT protein (p.Ala242Pro). This variant is present in population databases (rs766054124, gnomAD 0.004%). 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: 471901). 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 not expected to disrupt TERT protein function with a negative predictive value of 95%. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Dyskeratosis congenita Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2022 | The p.A242P variant (also known as c.724G>C), located in coding exon 2 of the TERT gene, results from a G to C substitution at nucleotide position 724. The alanine at codon 242 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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