chr5-1271132-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_198253.3(TERT):c.2455C>T(p.Arg819Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,834 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. R819S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: -0.143

Publications

1 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 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 5-1271132-G-A is Pathogenic according to our data. Variant chr5-1271132-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265268.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TERT	NM_198253.3 link	c.2455C>T	p.Arg819Cys	missense_variant	Exon 8 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 link	c.2455C>T	p.Arg819Cys	missense_variant	Exon 8 of 15		NP_001180305.1
TERT	NR_149162.3 link	n.2366-2499C>T		intron_variant	Intron 6 of 12
TERT	NR_149163.3 link	n.2330-2499C>T		intron_variant	Intron 6 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.2455C>T	p.Arg819Cys	missense_variant	Exon 8 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248072

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460574

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726562

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111906

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000131

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41474

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita

Uncertain:2

Dec 17, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Jun 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R819C variant (also known as c.2455C>T), located in coding exon 8 of the TERT gene, results from a C to T substitution at nucleotide position 2455. The arginine at codon 819 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported as de novo and co-occurred with another TERT variant in an individual diagnosed with dyskeratosis congenita (Vanderver A et al. Ann Neurol, 2016 Jun;79:1031-1037). This variant was also identified in 70-year-old female acute myeloid leukemia patient (Gurnari C et al. Hematol Oncol, 2022 Oct;40:812-817).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided

Pathogenic:1

Jul 20, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R819C variant in the TERT gene has been reported in an abstract by Iannotti et al. (2013) in an adult female with abnormal skin pigmentation, familial pulmonary fibrosis, osteoarthritis, and a refractory cytopenia with multilineage dysplasia with a 47,XX,+8 karyotype. This variant was identified via direct sequencing of the TERT gene. A second variant in the TERT gene was also observed in the reported individual in the heterozygous state (Iannotti et al., 2013); it is unclear from the abstract if segregation analysis was performed to confirm the phase of these variants in this individual. The R819C variant has also been reported previously in this individual as a de novo finding in association with dyskeratosis congenita (Vanderver et al., 2016). The R819C variant is a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a residue that is not conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Data from control individuals were not available to assess whether the R819C variant is a common benign variant in the general population. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret R819C as a likely pathogenic variant.

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

Uncertain:1

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense change has been observed in individual(s) with atypical dyskeratosis congenita with hypomyelination (PMID: 27159321). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 819 of the TERT protein (p.Arg819Cys). This variant is present in population databases (no rsID available, gnomAD 0.005%). ClinVar contains an entry for this variant (Variation ID: 265268). 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. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

-0.14

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.71

ClinPred

0.99

GERP RS

-1.7

Varity_R

0.53

gMVP

0.72

Mutation Taster

=85/15

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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