5-1293971-C-T

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.915G>A(p.Ala305Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,558,002 control chromosomes in the GnomAD database, including 62,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A305A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 4300 hom., cov: 34)

Exomes 𝑓: 0.28 ( 58165 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:3

Conservation

PhyloP100: -1.61

Publications

273 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=-0.66).

BP6

Variant 5-1293971-C-T is Benign according to our data. Variant chr5-1293971-C-T is described in ClinVar as Benign. ClinVar VariationId is 39126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.915G>A	p.Ala305Ala	synonymous_variant	Exon 2 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.915G>A	p.Ala305Ala	synonymous_variant	Exon 2 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.994G>A		non_coding_transcript_exon_variant	Exon 2 of 13
TERT	NR_149163.3 link	n.994G>A		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TERT	ENST00000310581.10 link	c.915G>A	p.Ala305Ala	synonymous_variant	Exon 2 of 16	1	NM_198253.3	ENSP00000309572.5	O14746-1
TERT	ENST00000334602.10 link	c.915G>A	p.Ala305Ala	synonymous_variant	Exon 2 of 15	1		ENSP00000334346.6	O14746-3
TERT	ENST00000460137.6 link	n.915G>A		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000425003.1	O14746-4
TERT	ENST00000656021.1 link	n.915G>A		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000499759.1	A0A590UK92

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33875

AN:

152012

Hom.:

4301

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.359

Gnomad SAS

AF:

0.459

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.242

GnomAD2 exomes

AF:

0.287

AC:

47433

AN:

165404

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.368

Gnomad FIN exome

AF:

0.216

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.276

GnomAD4 exome

AF:

0.281

AC:

394774

AN:

1405872

Hom.:

58165

Cov.:

AF XY:

0.287

AC XY:

199470

AN XY:

695238

show subpopulations

African (AFR)

AF:

0.100

AC:

3206

AN:

31918

American (AMR)

AF:

0.206

AC:

7712

AN:

37376

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

7012

AN:

25294

East Asian (EAS)

AF:

0.301

AC:

10868

AN:

36108

South Asian (SAS)

AF:

0.478

AC:

38345

AN:

80226

European-Finnish (FIN)

AF:

0.211

AC:

9266

AN:

43812

Middle Eastern (MID)

AF:

0.297

AC:

1699

AN:

5718

European-Non Finnish (NFE)

AF:

0.276

AC:

300258

AN:

1086980

Other (OTH)

AF:

0.281

AC:

16408

AN:

58440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

21725

43450

65174

86899

108624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10264

20528

30792

41056

51320

<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:

0.223

AC:

33879

AN:

152130

Hom.:

4300

Cov.:

AF XY:

0.224

AC XY:

16634

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.108

AC:

4503

AN:

41536

American (AMR)

AF:

0.199

AC:

3039

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

972

AN:

3466

East Asian (EAS)

AF:

0.359

AC:

1852

AN:

5160

South Asian (SAS)

AF:

0.458

AC:

2205

AN:

4818

European-Finnish (FIN)

AF:

0.208

AC:

2198

AN:

10588

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18255

AN:

67946

Other (OTH)

AF:

0.251

AC:

530

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1349

2699

4048

5398

6747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.258

Hom.:

3590

Bravo

AF:

0.214

Asia WGS

AF:

0.402

AC:

1398

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:3

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

Ala305Ala in exon 2 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 26.0% (2202/8480) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2736098). -

Apr 01, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

not provided

Benign:3Other:1

Nov 22, 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

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Jan 13, 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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aplastic anemia

Benign:1Other:1

Radiation Cancer Biology Lab, University of Rajasthan Jaipur

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

- -

Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2

Benign:1

Jan 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita

Benign:1

Dec 24, 2014

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

-0.66

CADD

Benign

3.8

(source)

DANN

Benign

0.73

PhyloP100

-1.6

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