chr5-1294797-G-C

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>G(p.Pro65Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000984 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:1

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=0.26552075).

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>G	p.Pro65Ala	missense	Exon 1 of 16	NP_937983.2
TERT	NM_001193376.3		c.193C>G	p.Pro65Ala	missense	Exon 1 of 15	NP_001180305.1
TERT	NR_149162.3		n.272C>G		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>G	p.Pro65Ala	missense	Exon 1 of 16	ENSP00000309572.5
TERT	ENST00000334602.10	TSL:1	c.193C>G	p.Pro65Ala	missense	Exon 1 of 15	ENSP00000334346.6
TERT	ENST00000460137.6	TSL:1	n.193C>G		non_coding_transcript_exon	Exon 1 of 13	ENSP00000425003.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000167

AC:

AN:

119432

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000858

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:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1372134

Hom.:

Cov.:

AF XY:

0.00000591

AC XY:

AN XY:

677132

show subpopulations

African (AFR)

AF:

0.0000678

AC:

AN:

29506

American (AMR)

AF:

0.0000572

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:

0.00

AC:

AN:

1075800

Other (OTH)

AF:

0.0000175

AC:

AN:

57260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

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:

0.0000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41576

American (AMR)

AF:

0.0000654

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:

0.00

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000113

ExAC

AF:

0.0000119

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Pathogenic:1Uncertain:2

Jul 20, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This TERT variant has been reported in patients presenting with cirrhosis and acute myeloid leukemia with aplastic anemia. Functional studies showed that this variant significantly reduces telomerase activity compared to the wildtype. TERT c.193C>G is located in the RNA-interaction domain within the N-terminal extension region. This variant (rs544215765) has a ClinVar entry, and is shown rare (<0.1%) in a large population dataset (gnomAD: 3/150704 total alleles; 0.002%; no homozygotes), however this frequency estimate may not be reliable due to low coverage at this position in gnomAD exomes. We consider this variant to be likely pathogenic.

Feb 11, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 supporting, PP2 supporting, BP4 supporting

Oct 11, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyskeratosis congenita

Uncertain:2

Dec 20, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

Dec 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P65A variant (also known as c.193C>G), located in coding exon 1 of the TERT gene, results from a C to G substitution at nucleotide position 193. The proline at codon 65 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

not provided

Uncertain:1

Nov 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies are conflicting: some demonstrate reduced or absent telomerase activity and reduced cell growth compared to wildtype, while others failed to show significant reductions in telomerase activity and processivity (PMID: 19147845, 21520174, 23901009); Reported in the germline of individuals with aplastic anemia, myelodysplastic syndrome, and/or liver cirrhosis (PMID: 21520174, 30523342, 35969835); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30995915, 19796246, 19636400, 23901009, 19147845, 21520174, 23716176, 35969835, 30523342)

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

Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.091

MutationAssessor

Uncertain

2.4

PhyloP100

0.88

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.31

Sift

Benign

0.26

Sift4G

Benign

0.083

Polyphen

0.056

Vest4

0.16

MutPred

0.52

Loss of glycosylation at P65 (P = 0.0085)

MVP

0.73

MPC

1.1

ClinPred

0.089

GERP RS

3.1

PromoterAI

0.018

Neutral

(source)

Varity_R

0.087

gMVP

0.42

Mutation Taster

=77/23

disease causing (ClinVar)

(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