rs1060503011

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671Q) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.403

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita, autosomal dominant 2
Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
acute myeloid leukemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma, cutaneous malignant, susceptibility to, 9
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 30 uncertain in NM_198253.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-1279410-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436994.

PP5

Variant 5-1279410-G-A is Pathogenic according to our data. Variant chr5-1279410-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 410693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

154284

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000500

AC:

AN:

1400060

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

691046

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31732

American (AMR)

AF:

0.00

AC:

AN:

36048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25216

East Asian (EAS)

AF:

0.00

AC:

AN:

36030

South Asian (SAS)

AF:

0.00

AC:

AN:

79410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.00000555

AC:

AN:

1081270

Other (OTH)

AF:

0.00

AC:

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

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

Pathogenic:1

May 10, 2025

Ambry Genetics

Significance:Likely pathogenic

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 identified in the heterozygous or homozygous state in individuals with features consistent with TERT-related disorder (Diaz de Leon A et al. PLoS One, 2010 May;5:e10680; Newton CA et al. Eur Respir J, 2016 Dec;48:1710-1720; Snetselaar R et al. PLoS One, 2017 Dec;12:e0189467; Arias-Salgado EG et al. Orphanet J Rare Dis, 2019 Apr;14:82; Çepni E et al. Am J Med Genet A, 2022 Apr;188:1226-1232; Manali ED et al. Respiration, 2022 Jan;101:531-543). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

(source)

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

PhyloP100

0.40

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

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over