rs483352771
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_198253.3(TERT):c.2354C>T(p.Pro785Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,740 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. P785A) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2354C>T | p.Pro785Leu | missense_variant | 7/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.2354C>T | p.Pro785Leu | missense_variant | 7/15 | ||
TERT | NR_149162.3 | n.2366-3580C>T | intron_variant, non_coding_transcript_variant | ||||
TERT | NR_149163.3 | n.2330-3580C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.2354C>T | p.Pro785Leu | missense_variant | 7/16 | 1 | NM_198253.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152244Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246970Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134522
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460380Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726444
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74504
ClinVar
Submissions by phenotype
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 785 of the TERT protein (p.Pro785Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with acute myeloid leukemia and aplastic anemia (PMID: 19760749, 30523342). ClinVar contains an entry for this variant (Variation ID: 846805). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TERT function (PMID: 19760749, 26887940). 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 | Oct 12, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are conflicting: while telomerase activity and TERT function were demonstrated to be increased in comparison to wild-type in one study, they were demonstrated to be decreased in another (Kirwan et al., 2009; Chu et al., 2016); Observed in individuals with myelodysplastic syndrome, acute myeloid leukemia, and/or aplastic anemia, as well as in clinically unaffected family members; notably, all heterozygous carriers had reduced telomere length (Kirwan et al., 2009; Holme et al., 2012; Gutierrez et al., 2019); This variant is associated with the following publications: (PMID: 26887940, 19760749, 22533337, 30523342) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at