5-1294378-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_198253.3(TERT):c.508G>A(p.Val170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,426,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
TERT
NM_198253.3 missense
NM_198253.3 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 0.708
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 5 ACMG points.
PM1
In a region_of_interest RNA-interacting domain 1 (size 229) in uniprot entity TERT_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_198253.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.785
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.508G>A | p.Val170Met | missense_variant | 2/16 | ENST00000310581.10 | NP_937983.2 | |
TERT | NM_001193376.3 | c.508G>A | p.Val170Met | missense_variant | 2/15 | NP_001180305.1 | ||
TERT | NR_149162.3 | n.587G>A | non_coding_transcript_exon_variant | 2/13 | ||||
TERT | NR_149163.3 | n.587G>A | non_coding_transcript_exon_variant | 2/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TERT | ENST00000310581.10 | c.508G>A | p.Val170Met | missense_variant | 2/16 | 1 | NM_198253.3 | ENSP00000309572 | P2 | |
TERT | ENST00000334602.10 | c.508G>A | p.Val170Met | missense_variant | 2/15 | 1 | ENSP00000334346 | A2 | ||
TERT | ENST00000460137.6 | c.508G>A | p.Val170Met | missense_variant, NMD_transcript_variant | 2/13 | 1 | ENSP00000425003 | |||
TERT | ENST00000656021.1 | c.508G>A | p.Val170Met | missense_variant, NMD_transcript_variant | 2/17 | ENSP00000499759 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD3 exomes AF: 0.00000535 AC: 1AN: 186834Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 104316
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GnomAD4 exome AF: 0.0000266 AC: 38AN: 1426780Hom.: 0 Cov.: 35 AF XY: 0.0000254 AC XY: 18AN XY: 708630
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GnomAD4 genome Cov.: 34
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 26, 2011 | - - |
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 170 of the TERT protein (p.Val170Met). This variant is present in population databases (rs387907248, gnomAD 0.001%). This missense change has been observed in individual(s) with aplastic anemia and pulmonary fibrosis (PMID: 21436073, 24833766, 35776903). ClinVar contains an entry for this variant (Variation ID: 36947). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 21436073). 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. - |
Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2022 | - - |
Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2023 | - - |
TERT-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 13, 2023 | The TERT c.508G>A variant is predicted to result in the amino acid substitution p.Val170Met. This variant has been reported in several individuals with aplastic anaemia and pulmonary fibrosis (Parry et al. 2011. PubMed ID: 21436073; Silhan et al. 2014. PubMed ID: 24833766; Gutierrez-Rodrigues et al. 2018. PubMed ID: 30523342). Telomerase activity assay showed that this variant may decrease enzyme activity (Parry et al. 2011. PubMed ID: 21436073). This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1294493-C-T). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at P173 (P = 0.1645);Gain of glycosylation at P173 (P = 0.1645);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at