rs1060503011

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671G) has been classified as Likely pathogenic.

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:5U: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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_198253.3

PM2

Very rare variant in population databases, with high coverage;

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 id is 436994.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

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: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr5-1279410-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TERT	NM_198253.3 linkuse as main transcript	c.2011C>T	p.Arg671Trp	missense_variant	5/16	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.2011C>T	p.Arg671Trp	missense_variant	5/15
TERT	NR_149162.3 linkuse as main transcript	n.2090C>T		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3 linkuse as main transcript	n.2090C>T		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.2011C>T	p.Arg671Trp	missense_variant	5/16	1	NM_198253.3	P2	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:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Telomere syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Aug 01, 2022

- -

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 -

Autosomal recessive dyskeratosis congenita 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 07, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 23, 2019

PS3_Supporting, PS4_Moderate, PM2, PP2 -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Diseases Diagnostic Center, Koc University Hospital

Oct 02, 2021

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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2022

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 individual(s) with Hoyeraal Hreidarsson syndrome (PMID: 34890115). ClinVar contains an entry for this variant (Variation ID: 410693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TERT protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 20502709). 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. -

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

MutationTaster

Benign

1.0

N;N;N;N

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