NM_198253.3:c.3184G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_198253.3(TERT):c.3184G>A(p.Ala1062Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,612,636 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 33)

Exomes 𝑓: 0.020 ( 339 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:15O:2

Conservation

PhyloP100: -3.62

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:

ENSG00000287486 (HGNC:):

ENSG00000287486 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.053545833).

BP6

Variant 5-1254479-C-T is Benign according to our data. Variant chr5-1254479-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=5, Uncertain_significance=3, not_provided=1}. Variant chr5-1254479-C-T is described in Lovd as [Benign]. Variant chr5-1254479-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2031/152222) while in subpopulation NFE AF= 0.023 (1566/67986). AF 95% confidence interval is 0.0221. There are 24 homozygotes in gnomad4. There are 903 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.3184G>A	p.Ala1062Thr	missense_variant	Exon 15 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2995G>A	p.Ala999Thr	missense_variant	Exon 14 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2892G>A		non_coding_transcript_exon_variant	Exon 12 of 13
TERT	NR_149163.3 link	n.2856G>A		non_coding_transcript_exon_variant	Exon 12 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.3184G>A	p.Ala1062Thr	missense_variant	Exon 15 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2032

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0124

AC:

3056

AN:

246886

Hom.:

AF XY:

0.0123

AC XY:

1661

AN XY:

134680

show subpopulations

Gnomad AFR exome

AF:

0.00256

Gnomad AMR exome

AF:

0.00392

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0217

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0201

AC:

29410

AN:

1460414

Hom.:

339

Cov.:

AF XY:

0.0195

AC XY:

14178

AN XY:

726536

show subpopulations

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.00441

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00228

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.0244

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0133

AC:

2031

AN:

152222

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

903

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00380

Gnomad4 AMR

AF:

0.00719

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0131

Gnomad4 NFE

AF:

0.0230

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00336

AC:

ESP6500EA

AF:

0.0220

AC:

186

ExAC

AF:

0.0125

AC:

1507

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0199

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:15Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Mar 04, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Risk Allele. TERT c.3184G>A (p.Ala1062Thr) has been associated with increased risk for acute myeloid leukemia. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of non-Finnish European ancestry (2.1%, Genome Aggregation Database (gnomAD); rs35719940) and is present in ClinVar (ID: 39121). Several small studies implicate this variant is associated with a number of different hematological and pulmonary conditions including pulmonary fibrosis (Tsakiri 2007, Alder 2008), AML (Calado 2009, Aref 2014), DL-BCL and CLL (Hills 2009) and cirrhosis (Calado 2011). Functional studies from all but one group (Calado 2011) suggest that that this variant does not have a significant impact on telomerase activity (Alder 2008, Gramatges 2013, Zaug 2013, Zhang 2014, Hoffman 2017). In summary, it is uncertain if this variant is a risk factor for TERT-related conditions. -

Oct 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:2Benign:3

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TERT: PP2, BP4, BS1, BS2 -

Jul 09, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17460043, 22476886, 23538340, 23901009, 19147845, 18753630, 21520173, 25108601, 23716176, 27153395, 28813500, 28154186, 22093366, 15814878, 19796246, 24983628) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aplastic anemia

Benign:1Other:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyskeratosis congenita

Benign:1

Oct 24, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Breast carcinoma

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leukemia, acute myeloid, susceptibility to

Other:1

Jan 27, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.033

DANN

Benign

0.89

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.054

T;T

MetaSVM

Uncertain

-0.053

MutationAssessor

Benign

0.69

N;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.64

N;N

REVEL

Benign

0.21

Sift

Benign

0.75

T;T

Sift4G

Benign

0.22

T;D

Polyphen

0.34

B;B

Vest4

0.020

MPC

1.0

ClinPred

0.00055

GERP RS

-8.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.067

gMVP

0.041

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