5-1294378-C-T

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

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 0.708
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]

Genome browser will be placed here

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
TERTNM_198253.3 linkuse as main transcriptc.508G>A p.Val170Met missense_variant 2/16 ENST00000310581.10 NP_937983.2
TERTNM_001193376.3 linkuse as main transcriptc.508G>A p.Val170Met missense_variant 2/15 NP_001180305.1
TERTNR_149162.3 linkuse as main transcriptn.587G>A non_coding_transcript_exon_variant 2/13
TERTNR_149163.3 linkuse as main transcriptn.587G>A non_coding_transcript_exon_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.508G>A p.Val170Met missense_variant 2/161 NM_198253.3 ENSP00000309572 P2O14746-1
TERTENST00000334602.10 linkuse as main transcriptc.508G>A p.Val170Met missense_variant 2/151 ENSP00000334346 A2O14746-3
TERTENST00000460137.6 linkuse as main transcriptc.508G>A p.Val170Met missense_variant, NMD_transcript_variant 2/131 ENSP00000425003 O14746-4
TERTENST00000656021.1 linkuse as main transcriptc.508G>A p.Val170Met missense_variant, NMD_transcript_variant 2/17 ENSP00000499759

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000535
AC:
1
AN:
186834
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
104316
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000123
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000266
AC:
38
AN:
1426780
Hom.:
0
Cov.:
35
AF XY:
0.0000254
AC XY:
18
AN XY:
708630
show subpopulations
Gnomad4 AFR exome
AF:
0.0000302
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000336
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.0000113
ExAC
AF:
0.00000868
AC:
1

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 providedliterature onlyOMIMMay 26, 2011- -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 07, 2022- -
Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJun 22, 2023- -
TERT-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 13, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.59
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.3
M;M
MutationTaster
Benign
0.97
D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-2.0
N;N
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.98
D;D
Vest4
0.59
MutPred
0.29
Gain of glycosylation at P173 (P = 0.1645);Gain of glycosylation at P173 (P = 0.1645);
MVP
0.98
MPC
2.2
ClinPred
0.80
D
GERP RS
2.4
Varity_R
0.18
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs387907248; hg19: chr5-1294493; API