5-1279341-C-T

Position:

chr5-1279341-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_198253.3(TERT):c.2080G>A(p.Val694Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,584,256 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V694E) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 0.292

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_198253.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 5-1279341-C-T is Pathogenic according to our data. Variant chr5-1279341-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12731.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr5-1279341-C-T 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.2080G>A	p.Val694Met	missense_variant	5/16	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.2080G>A	p.Val694Met	missense_variant	5/15
TERT	NR_149162.3 linkuse as main transcript	n.2159G>A		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3 linkuse as main transcript	n.2159G>A		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.2080G>A	p.Val694Met	missense_variant	5/16	1	NM_198253.3	P2	O14746-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000349

AC:

AN:

1432078

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

709868

show subpopulations

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:

0.00000455

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 694 of the TERT protein (p.Val694Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TERT-related conditions (PMID: 15814878, 18635888; Invitae). ClinVar contains an entry for this variant (Variation ID: 12731). 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: 15814878, 23901009). 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. -

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 -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 07, 2005

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16990594, 25906514, 20502709, 23618685, 23538340, 16207588, 17825470, 20044353, 23901009, 25244922, 19636400, 19760749, 15814878, 18635888, 23716176, 20301779, 34019641, 31943309, 36496180) -

Dyskeratosis congenita

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2016

The p.V694M variant (also known as c.2080G>A), located in coding exon 5 of the TERT gene, results from a G to A substitution at nucleotide position 2080. The valine at codon 694 is replaced by methionine, an amino acid with highly similar properties. This alteration was first identified in a 34-year old male with moderate aplastic anemia, a family history of myelodysplastic syndrome, and markedly shortened telomeres in peripheral-blood leukocytes (Yamaguchi H et al. N. Engl. J. Med. 2005; 352:1413-24). This alteration has also been observed in an individual with idiopathic pulmonary fibrosis (Cronkhite JT et al. Am. J. Respir. Crit. Care Med. 2008; 178:729-37). Functional studies have found this variant to cause a reduction in telomerase activity when compared to wild type; however, processivity was not affected or increased when compared to wild type (Xie M et al. Nucleic Acids Res. 2010; 38:1982-96, 5:e10680, Zaug AJ et al. Nucleic Acids Res. 2013; 41:8969-78). This variant was previously reported in the SNPDatabase as rs121918662. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

TERT-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2022

The TERT c.2080G>A variant is predicted to result in the amino acid substitution p.Val694Met. This variant was reported in an individual with aplastic anemia and shortened telomeres and a family history of myelodysplastic syndrome (Yamaguchi et al. 2005. PubMed ID: 15814878). This variant has also been reported in an individual with a personal and family history of pulmonary fibrosis (Cronkhite et al. 2008. PubMed ID: 18635888). Functional studies found this variant resulted in decreased telomerase activity; however, studies disagreed as to the extent of the decrease ranging from <1% to ~40% compared to wild type (Yamaguchi et al. 2005. PubMed ID: 15814878; Zaug et al. 2013. PubMed ID: 23901009). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Aplastic anemia

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.058

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

0.94

N;N;N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.77

Gain of MoRF binding (P = 0.096);Gain of MoRF binding (P = 0.096);

MVP

0.98

MPC

2.2

ClinPred

0.87

GERP RS

2.9

Varity_R

0.12

gMVP

0.88

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