NM_198253.3:c.2011C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_198253.3(TERT):c.2011C>T(p.Arg671Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,552,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 0.403

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;

PP5

Variant 5-1279410-G-A is Pathogenic according to our data. Variant chr5-1279410-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410693.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr5-1279410-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.2011C>T	p.Arg671Trp	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2011C>T	p.Arg671Trp	missense_variant	Exon 5 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2090C>T		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3 link	n.2090C>T		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.2011C>T	p.Arg671Trp	missense_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

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:

0.00

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:

0.00000500

AC:

AN:

1400060

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

691046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000315

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:

0.00000555

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

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

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 17, 2024

GeneDx

Significance: Likely pathogenic

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; This variant is associated with the following publications: (PMID: 33006015, 35078193, 20502709, 30995915, 34890115) -

Sep 23, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Supporting, PS4_Moderate, PM2, PP2 -

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

Pathogenic:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 671 of the TERT protein (p.Arg671Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Hoyeraal Hreidarsson syndrome and autosomal dominant pulmonary fibrosis (PMID: 20502709, 34890115, 35078193). ClinVar contains an entry for this variant (Variation ID: 410693). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 20502709). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Telomere syndrome

Pathogenic:1

Aug 01, 2022

The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 -

Autosomal recessive dyskeratosis congenita 4

Pathogenic:1

Jul 07, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hoyeraal-Hreidarsson syndrome;C3151444:Autosomal recessive dyskeratosis congenita 4

Pathogenic:1

Oct 02, 2021

Genetic Diseases Diagnostic Center, Koc University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The Arg671Trp variant in TERT was previously reported in heterozygous state in two kindred with familial pulmonary fibrosis and shown to reduce in vitro telomerase activity (Diaz de Leon, 2010). Identified variant was neither reported in 1000 Genomes Project, GnomAD (including ExAC), CentoMD nor ESP databases and predicted to be deleterious by SIFT and possibly damaging by Polyphen-2 prediction tools; ClinVar classed as a variant of unknown significance (VUS). The p.Arg671Trp variant impedes the second amino acid of the motif 3b that is highly conserved among RTs, most likely affecting the template realignment during RNA/DNA duplex formation, thus the telomere repeat addition rate and processivity (Xie, 2010). Conservation of the arginine at this position among species suggests its necessity for proper telomerase function. Concordant with the cases published up-to-date, localization of this homozygous mutation in a highly conserved residue within TERT may explain the observed severe clinical phenotype (Marrone, 2007; Gramatges, 2013; Vogiatzi, 2013). Furthermore in our experience, p.Arg671Trp variant segregated with short telomere lengths and was associated with full-blown, overlapping HHS/DC phenotype in the proband; and heterogeneous adult-onset manifestations in heterozygous individuals. -

Dyskeratosis congenita

Uncertain:1

Jun 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R671W variant (also known as c.2011C>T), located in coding exon 5 of the TERT gene, results from a C to T substitution at nucleotide position 2011. The arginine at codon 671 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in individuals with interstitial pneumonia (Snetselaar R et al. PLoS One, 2017 Dec;12:e0189467) and pulmonary fibrosis (Diaz de Leon A et al. PLoS One, 2010 May;5:e10680; Newton CA et al. Eur Respir J, 2016 Dec;48:1710-1720; Maryoung L et al. J Clin Invest, 2017 Mar;127:982-986; Aria). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.025

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.58

Sift

Benign

0.034

D;D

Sift4G

Uncertain

0.032

D;D

Polyphen

1.0

D;D

Vest4

0.33

MutPred

0.53

Loss of methylation at R671 (P = 0.0327);Loss of methylation at R671 (P = 0.0327);

MVP

0.97

MPC

2.0

ClinPred

0.96

GERP RS

1.8

Varity_R

0.062

gMVP

0.77

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