rs368430301

Positions:

chr5-1279407-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198253.3(TERT):c.2014C>T(p.Arg672Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000599 in 1,552,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.462

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:

TERT (HGNC:):

TERT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3 linkuse as main transcript	c.2014C>T	p.Arg672Cys	missense_variant	5/16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 linkuse as main transcript	c.2014C>T	p.Arg672Cys	missense_variant	5/15		NP_001180305.1	O14746-3
TERT	NR_149162.3 linkuse as main transcript	n.2093C>T		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3 linkuse as main transcript	n.2093C>T		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.2014C>T	p.Arg672Cys	missense_variant	5/16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

154134

Hom.:

AF XY:

0.0000603

AC XY:

AN XY:

82922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000898

Gnomad SAS exome

AF:

0.0000872

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000676

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000429

AC:

AN:

1399994

Hom.:

Cov.:

AF XY:

0.0000434

AC XY:

AN XY:

691114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000554

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.0000629

Gnomad4 FIN exome

AF:

0.0000626

Gnomad4 NFE exome

AF:

0.0000435

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.000217

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000757

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000640

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 672 of the TERT protein (p.Arg672Cys). This variant is present in population databases (rs368430301, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of dyskeratosis congenita (PMID: 26136524, 30426156). ClinVar contains an entry for this variant (Variation ID: 471846). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with bone marrow failure and/or MDS or leukemia, at least one of whom had no features of dyskeratosis congenita on thorough examination (PMID: 26136524, 30426156, 31839986, 35106810); This variant is associated with the following publications: (PMID: 26136524, 30426156, 35106810, 31839986) -

TERT-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

The TERT c.2014C>T variant is predicted to result in the amino acid substitution p.Arg672Cys. This variant has been reported in the heterozygous state in three individuals with features of dyskeratosis congenita (Ghemlas et al. 2015. PubMed ID: 26136524, suppl materials; Akram et al. 2018. PubMed ID: 30426156). This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;.

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

2.0

M;M

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.44

Sift

Benign

0.10

T;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.53

MVP

0.80

MPC

1.4

ClinPred

0.36

GERP RS

3.8

Varity_R

0.13

gMVP

0.85

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