rs1554043029

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.217
Variant links:
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
TERTNM_198253.3 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant 2/16 ENST00000310581.10
TERTNM_001193376.3 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant 2/15
TERTNR_149162.3 linkuse as main transcriptn.727_728delinsAA non_coding_transcript_exon_variant 2/13
TERTNR_149163.3 linkuse as main transcriptn.727_728delinsAA non_coding_transcript_exon_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant 2/161 NM_198253.3 P2O14746-1
TERTENST00000334602.10 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant 2/151 A2O14746-3
TERTENST00000460137.6 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant, NMD_transcript_variant 2/131 O14746-4
TERTENST00000656021.1 linkuse as main transcriptc.648_649delinsAA p.Pro217Thr missense_variant, NMD_transcript_variant 2/17

Frequencies

GnomAD3 genomes
Cov.:
34
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
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 submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 15, 2021DNA 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 13, 2022This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554043029; hg19: chr5-1294352; API