rs1554039721

Variant names:

• chr5-1268521-C-T
• rs1554039721
• NM_198253.3:c.2581G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_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: Splicing: ADA: 0.07369
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 6.97

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]

ACMG classification

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
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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2581G>A	p.Gly861Arg	missense_variant, splice_region_variant	Exon 9 of 16	1	NM_198253.3	ENSP00000309572.5

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

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:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

not specified Uncertain:1

Feb 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 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

Other links and lift over

dbSNP: rs1554039721; hg19: chr5-1268636;