rs368430301

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672H) has been classified as Likely benign.

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:4

Conservation

PhyloP100: 0.462

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita, autosomal dominant 2
Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
acute myeloid leukemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma, cutaneous malignant, susceptibility to, 9
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 25 uncertain in NM_198253.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.2014C>T	p.Arg672Cys	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2014C>T	p.Arg672Cys	missense_variant	Exon 5 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2093C>T		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3 link	n.2093C>T		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.2014C>T	p.Arg672Cys	missense_variant	Exon 5 of 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

GnomAD2 exomes

AF:

0.0000519

AC:

AN:

154134

AF XY:

0.0000603

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 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

African (AFR)

AF:

0.00

AC:

AN:

31736

American (AMR)

AF:

0.0000554

AC:

AN:

36104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.0000277

AC:

AN:

36040

South Asian (SAS)

AF:

0.0000629

AC:

AN:

79438

European-Finnish (FIN)

AF:

0.0000626

AC:

AN:

47938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4300

European-Non Finnish (NFE)

AF:

0.0000435

AC:

AN:

1081298

Other (OTH)

AF:

0.0000345

AC:

AN:

57946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000217

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. 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

Feb 07, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Dyskeratosis congenita

Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R672C variant (also known as c.2014C>T), located in coding exon 5 of the TERT gene, results from a C to T substitution at nucleotide position 2014. The arginine at codon 672 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

TERT-related disorder

Uncertain:1

Jan 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.46

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

Mutation Taster

=12/88

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over