rs33956095

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_198253.3(TERT):c.2031C>T(p.Gly677Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,557,728 control chromosomes in the GnomAD database, including 158 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. G677G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 51 hom., cov: 34)

Exomes 𝑓: 0.010 ( 107 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.69

Publications

9 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=-0.78).

BP6

Variant 5-1279390-G-A is Benign according to our data. Variant chr5-1279390-G-A is described in ClinVar as Benign. ClinVar VariationId is 227096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.69 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0201 (3061/152282) while in subpopulation AFR AF = 0.0467 (1941/41554). AF 95% confidence interval is 0.045. There are 51 homozygotes in GnomAd4. There are 1526 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 51 AR,AD,SD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.2031C>T	p.Gly677Gly	synonymous_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2031C>T	p.Gly677Gly	synonymous_variant	Exon 5 of 15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2110C>T		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3 link	n.2110C>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.2031C>T	p.Gly677Gly	synonymous_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

3050

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00998

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0101

AC:

1602

AN:

158400

AF XY:

0.00941

show subpopulations

Gnomad AFR exome

AF:

0.0543

Gnomad AMR exome

AF:

0.00736

Gnomad ASJ exome

AF:

0.00153

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00851

GnomAD4 exome

AF:

0.0103

AC:

14514

AN:

1405446

Hom.:

107

Cov.:

AF XY:

0.0100

AC XY:

6941

AN XY:

694318

show subpopulations

African (AFR)

AF:

0.0496

AC:

1583

AN:

31902

American (AMR)

AF:

0.00750

AC:

275

AN:

36670

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

25246

East Asian (EAS)

AF:

0.000220

AC:

AN:

36398

South Asian (SAS)

AF:

0.00405

AC:

323

AN:

79718

European-Finnish (FIN)

AF:

0.0123

AC:

596

AN:

48324

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

4328

European-Non Finnish (NFE)

AF:

0.0102

AC:

11044

AN:

1084666

Other (OTH)

AF:

0.0101

AC:

589

AN:

58194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

951

1902

2853

3804

4755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.0201

AC:

3061

AN:

152282

Hom.:

Cov.:

AF XY:

0.0205

AC XY:

1526

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0467

AC:

1941

AN:

41554

American (AMR)

AF:

0.0116

AC:

177

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00394

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0127

AC:

135

AN:

10626

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00998

AC:

679

AN:

68020

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

161

323

484

646

807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0118

Hom.:

Bravo

AF:

0.0210

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

Gly677Gly 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 4.1% (173/4212) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs33956095). -

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TERT: BP4, BP7, BS1, BS2 -

Sep 20, 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 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. -

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dyskeratosis congenita

Benign:1

Feb 03, 2016

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.7

(source)

DANN

Benign

0.65

PhyloP100

-2.7

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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