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
Consequence
NM_198253.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TERT | NM_198253.3 | c.2581G>A | p.Gly861Arg | missense_variant, splice_region_variant | Exon 9 of 16 | ENST00000310581.10 | NP_937983.2 | |
TERT | NM_001193376.3 | c.2581G>A | p.Gly861Arg | missense_variant, splice_region_variant | Exon 9 of 15 | NP_001180305.1 | ||
TERT | NR_149162.3 | n.2478G>A | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 13 | ||||
TERT | NR_149163.3 | n.2442G>A | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 13 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460752Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726690
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 13, 2025 | Variant 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This 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 submitter | clinical testing | GeneDx | Feb 21, 2023 | Not 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at