5-1279410-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP5BP4

The NM_198253.3(TERT):​c.2011C>G​(p.Arg671Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TERT
NM_198253.3 missense

Scores

2
7
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.403
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-1279410-G-A is described in Lovd as [Pathogenic].
PP5
Variant 5-1279410-G-C is Pathogenic according to our data. Variant chr5-1279410-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436994.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.34420618). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.2011C>G p.Arg671Gly missense_variant Exon 5 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.2011C>G p.Arg671Gly missense_variant Exon 5 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.2090C>G non_coding_transcript_exon_variant Exon 5 of 13
TERTNR_149163.3 linkn.2090C>G non_coding_transcript_exon_variant Exon 5 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkc.2011C>G p.Arg671Gly missense_variant Exon 5 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Dyskeratosis congenita Pathogenic:1
May 18, 2017
Genetic Services Laboratory, University of Chicago
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Apr 16, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has not been reported in the literature in individuals with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 436994). This sequence change replaces arginine with glycine at codon 671 of the TERT protein (p.Arg671Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.025
N
LIST_S2
Benign
0.79
T;T
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.34
T;T
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Uncertain
0.46
Sift
Benign
0.21
T;T
Sift4G
Benign
0.12
T;T
Polyphen
0.77
P;P
Vest4
0.31
MutPred
0.49
Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);
MVP
0.73
MPC
1.8
ClinPred
0.68
D
GERP RS
1.8
Varity_R
0.11
gMVP
0.72

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: rs1060503011; hg19: chr5-1279525; API