5-1294797-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_198253.3(TERT):c.193C>A(p.Pro65Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000853 in 1,524,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P65A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 0.882

Publications

7 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: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38128066).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198253.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TERT	NM_198253.3	MANE Select	c.193C>A	p.Pro65Thr	missense	Exon 1 of 16	NP_937983.2
TERT	NM_001193376.3		c.193C>A	p.Pro65Thr	missense	Exon 1 of 15	NP_001180305.1
TERT	NR_149162.3		n.272C>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TERT	ENST00000310581.10	TSL:1 MANE Select	c.193C>A	p.Pro65Thr	missense	Exon 1 of 16	ENSP00000309572.5
TERT	ENST00000334602.10	TSL:1	c.193C>A	p.Pro65Thr	missense	Exon 1 of 15	ENSP00000334346.6
TERT	ENST00000460137.6	TSL:1	n.193C>A		non_coding_transcript_exon	Exon 1 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000167

AC:

AN:

119432

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000429

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000276

GnomAD4 exome

AF:

0.00000729

AC:

AN:

1372134

Hom.:

Cov.:

AF XY:

0.00000738

AC XY:

AN XY:

677132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29506

American (AMR)

AF:

0.000143

AC:

AN:

34958

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24358

East Asian (EAS)

AF:

0.00

AC:

AN:

34726

South Asian (SAS)

AF:

0.00

AC:

AN:

77996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.00000465

AC:

AN:

1075800

Other (OTH)

AF:

0.00

AC:

AN:

57260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000197

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2110

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

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:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary fibrosis

Pathogenic:1

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance:Likely risk allele

Review Status:no assertion criteria provided

Collection Method:research

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted

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

Uncertain:1

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 65 of the TERT protein (p.Pro65Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with aplastic anemia (PMID: 30995915). ClinVar contains an entry for this variant (Variation ID: 471840). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.

Dyskeratosis congenita, autosomal dominant 2

Uncertain:1

Mar 20, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyskeratosis congenita

Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P65T variant (also known as c.193C>A), located in coding exon 1 of the TERT gene, results from a C to A substitution at nucleotide position 193. The proline at codon 65 is replaced by threonine, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other TERT variant(s) in individual(s) with features consistent with TERT-related disorder (Gutierrez-Rodrigues F et al. Genet Med, 2019 Jul;21:1594-1602; Gutierrez-Rodrigues F et al. Blood, 2023 Apr;141:2100-2113; Gutierrez-Rodrigues F et al. Blood, 2024 Dec;144:2402-2416; Arias-Salgado EG et al. Orphanet J Rare Dis, 2019 Apr;14:82; Silva JPL et al. Mol Biol Rep, 2024 Jun;51:754). This amino acid position is not 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.39

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.4

PhyloP100

0.88

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.40

Sift

Benign

0.14

Sift4G

Uncertain

0.049

Polyphen

0.82

Vest4

0.17

MutPred

0.54

Loss of catalytic residue at P64 (P = 0.0165)

MVP

0.78

MPC

1.5

ClinPred

0.19

GERP RS

3.1

PromoterAI

-0.00040

Neutral

(source)

Varity_R

0.11

gMVP

0.51

Mutation Taster

=74/26

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over