rs202123213

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198253.3(TERT):​c.2072G>A​(p.Arg691His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,581,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

3
10
6

Clinical Significance

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

Conservation

PhyloP100: 0.158
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TERTNM_198253.3 linkuse as main transcriptc.2072G>A p.Arg691His missense_variant 5/16 ENST00000310581.10 NP_937983.2
TERTNM_001193376.3 linkuse as main transcriptc.2072G>A p.Arg691His missense_variant 5/15 NP_001180305.1
TERTNR_149162.3 linkuse as main transcriptn.2151G>A non_coding_transcript_exon_variant 5/13
TERTNR_149163.3 linkuse as main transcriptn.2151G>A non_coding_transcript_exon_variant 5/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.2072G>A p.Arg691His missense_variant 5/161 NM_198253.3 ENSP00000309572 P2O14746-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152194
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000350
AC:
5
AN:
1429624
Hom.:
0
Cov.:
33
AF XY:
0.00000282
AC XY:
2
AN XY:
708458
show subpopulations
Gnomad4 AFR exome
AF:
0.0000611
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:
0.00000273
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152312
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000169
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 30, 2021In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 424177). This missense change has been observed in individual(s) with clinical features of TERT-related conditions (Invitae). This variant is present in population databases (rs202123213, ExAC 0.05%). This sequence change replaces arginine with histidine at codon 691 of the TERT protein (p.Arg691His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. -
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant in c.2072G>A(p.Arg691His) in TERT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg691His variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance (VUS). The amino acid Arg at position 691 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 07, 2017The R691H variant in the TERT gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R691H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R691H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R691H as a variant of uncertain significance. -
TERT-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 02, 2024The TERT c.2072G>A variant is predicted to result in the amino acid substitution p.Arg691His. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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
Benign
0.099
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.060
N
LIST_S2
Benign
0.84
T;T
M_CAP
Pathogenic
0.68
D
MetaRNN
Uncertain
0.56
D;D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
0.86
N;N;N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.016
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
1.0
D;D
Vest4
0.35
MVP
0.95
MPC
1.5
ClinPred
0.77
D
GERP RS
2.9
Varity_R
0.11
gMVP
0.78

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: rs202123213; hg19: chr5-1279464; COSMIC: COSV57209841; API