rs1554043029
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_198253.3(TERT):c.648_649delinsAA(p.Pro217Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L216L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Consequence
TERT
NM_198253.3 missense
NM_198253.3 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.217
Genes affected
TERT (HGNC:11730): (telomerase reverse transcriptase) Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.648_649delinsAA | p.Pro217Thr | missense_variant | 2/16 | ENST00000310581.10 | |
TERT | NM_001193376.3 | c.648_649delinsAA | p.Pro217Thr | missense_variant | 2/15 | ||
TERT | NR_149162.3 | n.727_728delinsAA | non_coding_transcript_exon_variant | 2/13 | |||
TERT | NR_149163.3 | n.727_728delinsAA | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.648_649delinsAA | p.Pro217Thr | missense_variant | 2/16 | 1 | NM_198253.3 | P2 | |
TERT | ENST00000334602.10 | c.648_649delinsAA | p.Pro217Thr | missense_variant | 2/15 | 1 | A2 | ||
TERT | ENST00000460137.6 | c.648_649delinsAA | p.Pro217Thr | missense_variant, NMD_transcript_variant | 2/13 | 1 | |||
TERT | ENST00000656021.1 | c.648_649delinsAA | p.Pro217Thr | missense_variant, NMD_transcript_variant | 2/17 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 15, 2021 | DNA sequence analysis of the TERT gene demonstrated a sequence change, c.648_649delinsAA, in exon 2 that results in an amino acid change, p.Pro217Thr. This sequence change is absent from known population databses (gnomAD). The p.Pro217Thr change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is not known to be functional. The p.Pro217Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with TERT-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Pro217Thr change remains unknown at this time. - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 13, 2022 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 217 of the TERT protein (p.Pro217Thr). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the 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: 539218). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at