rs1554039721

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_198253.3(TERT):​c.2581G>A​(p.Gly861Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense, splice_region

Scores

9
6
4
Splicing: ADA: 0.07369
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 6.97
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 Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a strand (size 12) in uniprot entity TERT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_198253.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TERTNM_198253.3 linkc.2581G>A p.Gly861Arg missense_variant, splice_region_variant Exon 9 of 16 ENST00000310581.10 NP_937983.2 O14746-1
TERTNM_001193376.3 linkc.2581G>A p.Gly861Arg missense_variant, splice_region_variant Exon 9 of 15 NP_001180305.1 O14746-3
TERTNR_149162.3 linkn.2478G>A splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 13
TERTNR_149163.3 linkn.2442G>A splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 13

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TERTENST00000310581.10 linkc.2581G>A p.Gly861Arg missense_variant, splice_region_variant Exon 9 of 16 1 NM_198253.3 ENSP00000309572.5 O14746-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460752
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726690
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000611
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria providedresearchGarcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical CenterJun 09, 2022Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 13, 2025Variant summary: TERT c.2581G>A (p.Gly861Arg) results in a non-conservative amino acid change located in the Reverse transcriptase (RT) catalytic domain profile (IPR000477) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250034 control chromosomes. c.2581G>A has been reported in the literature in multiple heterozygous individuals affected with TERT-related disorders, including dyskeratosis congenita, bone marrow failure syndrome, and telomere-related pulmonary fibrosis (example: Vulliamy_2011, Diaz de Leon_2011, Schratz_2020, Norris_2021, Zhang_2022, Tummala_2024). At-least one of these individuals inherited the variant from an asymptomatic mother (Vulliamy_2011). These data do not allow any conclusion about variant significance. One publication reports experimental evidence evaluating an impact on protein function. Specifically, an in vitro TRAP assay was utilized to measure residual telomerase activity and this variant showed a significantly reduced telomerase activity level at 1.0% of wild type (example: Vulliamy_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21349926, 33709208, 32076714, 39198715, 21931702, 36028256). ClinVar contains an entry for this variant (Variation ID: 471871). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 861 of the TERT protein (p.Gly861Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial pulmonary fibrosis and dyskeratosis congenita (PMID: 21349926, 21931702). ClinVar contains an entry for this variant (Variation ID: 471871). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TERT function (PMID: 21931702). 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 21, 2023Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced telomerase activity compared to wild type (Vulliamy et al., 2011); This variant is associated with the following publications: (PMID: 21349926, 21931702) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-5.4
D;D
REVEL
Pathogenic
0.80
Sift
Benign
0.041
D;D
Sift4G
Benign
0.070
T;T
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.58
Gain of MoRF binding (P = 0.0254);Gain of MoRF binding (P = 0.0254);
MVP
0.99
MPC
2.1
ClinPred
1.0
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.60
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.074
dbscSNV1_RF
Benign
0.28
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: rs1554039721; hg19: chr5-1268636; API