5-1254395-C-T

Position:

chr5-1254395-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_198253.3(TERT):c.3268G>A(p.Val1090Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7O:2

Conservation

PhyloP100: 0.297

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest CTE (size 196) in uniprot entity TERT_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_198253.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41590792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.3268G>A	p.Val1090Met	missense_variant	15/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.3079G>A	p.Val1027Met	missense_variant	14/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.2976G>A		non_coding_transcript_exon_variant	12/13
TERT	NR_149163.3 linkuse as main transcript	n.2940G>A		non_coding_transcript_exon_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.3268G>A	p.Val1090Met	missense_variant	15/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1
	ENST00000666708.1 linkuse as main transcript	n.289-279C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000522

AC:

AN:

249022

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1460962

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000441

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000851

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000473

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000578

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Feb 10, 2022	The TERT c.3268G>A (p.Val1090Met) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-1254510-C-T?dataset=gnomad_r2_1). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). In silico tools are not in agreement about the effect of this variant on protein function, but functional assays on this variant have shown telomere length shortening, reduced hematopoietic function and loss of telomerase activity (PS3; PMID: 15814878, 19796246, 26365799, 28154186). This variant has been observed in an individual with aplastic anemia (PMID: 15814878), hepatocellular carcinoma (PMID: 2881350) and one healthy carrier (PMID: 19561322). To our knowledge, this variant has not been reported in individuals with clinical features of dyskeratosis congenita. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PS3, PP2. -

Dyskeratosis congenita, autosomal dominant 2;C5561926:Interstitial lung disease 2

Uncertain:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 01-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2020	This sequence change replaces valine with methionine at codon 1090 of the TERT protein (p.Val1090Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs121918664, ExAC 0.03%). This variant has been observed in an individual affected with aplastic anaemia, and an unrelated individual affected with hepatocellular carcinoma, but was also observed in one healthy individual (PMID: 15814878, 28813500 19561322). ClinVar contains an entry for this variant (Variation ID: 12733). Experimental studies using a cell model have shown that this variant results in a reduction of telomerase activity (PMID: 15814878, 23901009, 19561322, 26365799, 28813500, 28154186). 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. -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 07, 2005

- -

Interstitial lung disease 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect: reduced telomere length and elongation capacity, as well as reduced telomerase activity and telomerase processivity (PMID: 15814878, 19561322, 28154186, 34019641); This variant is associated with the following publications: (PMID: 19796246, 19561322, 34019641, 28154186, 23901009, 26365799, 23538340, 20301779, 23716176, 16647572, 26851889, 28813500, 15814878) -

TERT-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2024

The TERT c.3268G>A variant is predicted to result in the amino acid substitution p.Val1090Met. This variant was reported in patients with aplastic anaemia (Yamaguchi et al. 2005. PubMed ID: 15814878) and hepatocellular carcinoma (Donaires et al. 2017. PubMed ID: 28813500). It has also been shown to reduce telomerase activity (Hoffman et al. 2017. PubMed ID: 28154186; Donaires et al. 2017. PubMed ID: 28813500; Table 3. Calado et al. 2009. PubMed ID: 19561322). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. At this time the clinical significance of this variant is uncertain due to lack of sufficient genetic and functional 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

Benign

0.11

BayesDel_addAF

Benign

0.0091

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.42

T;T

MetaSVM

Uncertain

0.050

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.65

N;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.068

T;T

Polyphen

0.99

D;D

Vest4

0.66

MVP

0.82

MPC

1.3

ClinPred

0.037

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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