chr5-1278750-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198253.3(TERT):c.2177C>T(p.Thr726Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1O:1

Conservation

PhyloP100: -0.0690

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]

TERT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.2177C>T	p.Thr726Met	missense_variant	Exon 6 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2177C>T	p.Thr726Met	missense_variant	Exon 6 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2256C>T		non_coding_transcript_exon_variant	Exon 6 of 13
TERT	NR_149163.3 link	n.2220C>T		non_coding_transcript_exon_variant	Exon 6 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.2177C>T	p.Thr726Met	missense_variant	Exon 6 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152236

Hom.:

Cov.:

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251478

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000982

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.0000773

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000701

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 31, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32487952, 32150348, 25562321, 23426163, 23901009, 26329388, 28813500, 26887940, 16990594, 21176016, 21323862, 17825470, 22775985, 35927969, 23716176, 16627250, 23538340, 36649908, 35106810) -

not specified

Uncertain:1

Apr 24, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the TERT gene demonstrated a sequence change, c.2177C>T, in exon 6 that results in an amino acid change, p.Thr726Met. This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European sub-population (dbSNP rs149566858). The p.Thr726Met change has been reported in individuals with aplastic anemia, dyskeratosis congenita, Hoyeraal Hreidarsson syndrome, and emphysema (PMID: 16627250, 25562321, 23538340, 26329388). This sequence change has also been identified in the unaffected parent of an individual with aplastic anemia (PMID: 16627250). The p.Thr726Met change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. The p.Thr726Met substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Some studies have demonstrated that the p.Thr726Met change does not significantly impact telomerase enzyme activity (PMID: 26887940, 23901009, 16990594), while others have reported impaired enzyme activity in presence of this variant (PMID: 25562321, 28813500). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr726Met change remains unknown at this time. -

Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9

Uncertain:1

Apr 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Interstitial lung disease 2

Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal dominant 2

Uncertain:1

Oct 15, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T726M variant (also known as c.2177C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2177. The threonine at codon 726 is replaced by methionine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with TERT-related disorder (Liang J et al. Haematologica, 2006 May;91:656-8; Yamaguchi H et al. Int J Hematol, 2015 Nov;102:544-52; Stanley SE et al. J Clin Invest, 2015 Feb;125:563-70; Gurnari C et al. Hematol Oncol, 2022 Oct;40:812-817; Janczar S et al. Pediatr Blood Cancer, 2022 Oct;69:e29909). The majority of functional studies suggest this variant does not have a significant impact on telomerase activity; however, the physiological relevance of this finding is unclear (Xin ZT et al. Blood, 2007 Jan;109:524-32; Zaug AJ et al. Nucleic Acids Res, 2013 Oct;41:8969-78; Stanley SE et al. J Clin Invest, 2015 Feb;125:563-70; Chu TW et al. J Biol Chem, 2016 Apr;291:8374-86; Donaires FS et al. PLoS One, 2017 Aug;12:e0183287). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

TERT-related disorder

Uncertain:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TERT c.2177C>T variant is predicted to result in the amino acid substitution p.Thr726Met. This variant has been reported in an individual with aplastic anemia, an individual with cirrhosis, alcoholism, and advanced hepatocellular carcinoma, an individual with emphysema who was a smoker, and an individual with dyskeratosis congenita (Liang et al. 2006. PubMed ID: 16627250; Table 2, Donaires. 2017. PubMed ID: 28813500; Table 3, Stanley. 2015. PubMed ID: 25562321; Table 2, Yamaguchi. 2015. PubMed ID: 26329388). Experimental studies provide conflicting evidence regarding the impact of this variant on telomerase activity (Figure 2, Donaires. 2017. PubMed ID: 28813500; Table 1, Gramatges et al. 2013. PubMed ID: 23538340; Stanley. 2015. PubMed ID: 25562321; Table 1, Zaug. 2013. PubMed ID: 23901009). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/39111/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal dominant 1

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Uncertain

0.050

CADD

Benign

1.9

DANN

Benign

0.97

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.55

T;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Uncertain

0.094

MutationAssessor

Benign

-0.69

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.83

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.14

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.42

B;P

Vest4

0.55

MVP

0.95

MPC

1.1

ClinPred

0.044

GERP RS

-8.4

Varity_R

0.015

gMVP

0.71

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over