rs33963617

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198253.3(TERT):c.2097C>T(p.Ala699Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 1,585,702 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 22 hom., cov: 33)

Exomes 𝑓: 0.0091 ( 147 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 0.147

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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 5-1279324-G-A is Benign according to our data. Variant chr5-1279324-G-A is described in ClinVar as Benign. ClinVar VariationId is 39107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.147 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TERT	NM_198253.3 link	c.2097C>T	p.Ala699Ala	synonymous_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 link	c.2097C>T	p.Ala699Ala	synonymous_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3 link	n.2176C>T		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3 link	n.2176C>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.2097C>T	p.Ala699Ala	synonymous_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1213

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.0708

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00797

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.0114

AC:

2269

AN:

198788

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00300

Gnomad ASJ exome

AF:

0.00728

Gnomad EAS exome

AF:

0.0808

Gnomad FIN exome

AF:

0.00291

Gnomad NFE exome

AF:

0.00748

Gnomad OTH exome

AF:

0.00821

GnomAD4 exome

AF:

0.00910

AC:

13043

AN:

1433384

Hom.:

147

Cov.:

AF XY:

0.00910

AC XY:

6470

AN XY:

710636

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

32916

American (AMR)

AF:

0.00285

AC:

116

AN:

40736

Ashkenazi Jewish (ASJ)

AF:

0.00722

AC:

185

AN:

25622

East Asian (EAS)

AF:

0.0484

AC:

1849

AN:

38228

South Asian (SAS)

AF:

0.00640

AC:

526

AN:

82182

European-Finnish (FIN)

AF:

0.00350

AC:

175

AN:

50050

Middle Eastern (MID)

AF:

0.00215

AC:

AN:

4184

European-Non Finnish (NFE)

AF:

0.00864

AC:

9504

AN:

1100272

Other (OTH)

AF:

0.0107

AC:

636

AN:

59194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

785

1569

2354

3138

3923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.00796

AC:

1212

AN:

152318

Hom.:

Cov.:

AF XY:

0.00804

AC XY:

599

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

41580

American (AMR)

AF:

0.00523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.0710

AC:

367

AN:

5170

South Asian (SAS)

AF:

0.00745

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00797

AC:

542

AN:

68010

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00662

Hom.:

Bravo

AF:

0.00772

Asia WGS

AF:

0.0350

AC:

121

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala699Ala in exon 5 of TERT: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 0.8% (65/8514) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs33963617). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aplastic anemia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Melanoma, cutaneous malignant, susceptibility to, 9

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyskeratosis congenita

Benign:1

Feb 07, 2017

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. -

Acute myeloid leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita, autosomal dominant 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.8

(source)

DANN

Benign

0.51

PhyloP100

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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