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rs2736098

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198253.3(TERT):c.915G>A(p.Ala305=) 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

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:3

Conservation

PhyloP100: -1.61
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 39126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1293971-C-T is described in Lovd as [Benign].
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/exons MANE UniProt
TERTNM_198253.3 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant 2/16 ENST00000310581.10
TERTNM_001193376.3 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant 2/15
TERTNR_149162.3 linkuse as main transcriptn.994G>A non_coding_transcript_exon_variant 2/13
TERTNR_149163.3 linkuse as main transcriptn.994G>A non_coding_transcript_exon_variant 2/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TERTENST00000310581.10 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant 2/161 NM_198253.3 P2O14746-1
TERTENST00000334602.10 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant 2/151 A2O14746-3
TERTENST00000460137.6 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant, NMD_transcript_variant 2/131 O14746-4
TERTENST00000656021.1 linkuse as main transcriptc.915G>A p.Ala305= synonymous_variant, NMD_transcript_variant 2/17

Frequencies

GnomAD3 genomes
AF:
0.223
AC:
33875
AN:
152012
Hom.:
4301
Cov.:
34
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
GnomAD3 exomes
AF:
0.287
AC:
47433
AN:
165404
Hom.:
7510
AF XY:
0.301
AC XY:
26820
AN XY:
89020
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 SAS exome
AF:
0.479
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.:
63
AF XY:
0.287
AC XY:
199470
AN XY:
695238
show subpopulations
Gnomad4 AFR exome
AF:
0.100
Gnomad4 AMR exome
AF:
0.206
Gnomad4 ASJ exome
AF:
0.277
Gnomad4 EAS exome
AF:
0.301
Gnomad4 SAS exome
AF:
0.478
Gnomad4 FIN exome
AF:
0.211
Gnomad4 NFE exome
AF:
0.276
Gnomad4 OTH exome
AF:
0.281
GnomAD4 genome
AF:
0.223
AC:
33879
AN:
152130
Hom.:
4300
Cov.:
34
AF XY:
0.224
AC XY:
16634
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.108
Gnomad4 AMR
AF:
0.199
Gnomad4 ASJ
AF:
0.280
Gnomad4 EAS
AF:
0.359
Gnomad4 SAS
AF:
0.458
Gnomad4 FIN
AF:
0.208
Gnomad4 NFE
AF:
0.269
Gnomad4 OTH
AF:
0.251
Alfa
AF:
0.261
Hom.:
3107
Bravo
AF:
0.214
Asia WGS
AF:
0.402
AC:
1398
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:17Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 01, 2016- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This 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. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Ala305Ala 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). -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:2Other:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 16, 2023- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-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. -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Dyskeratosis congenita, autosomal dominant 2 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 14, 2021- -
Aplastic anemia Benign:1Other:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided, no classification providedliterature onlyRadiation Cancer Biology Lab, University of Rajasthan Jaipur-- -
Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 24, 2014This alteration is classified as benign based on a combination of the following: 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. -
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
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 28, 2022- -
Acute myeloid leukemia Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Dyskeratosis congenita, autosomal dominant 1 Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.66
Cadd
Benign
3.8
Dann
Benign
0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2736098; hg19: chr5-1294086; COSMIC: COSV57199189; COSMIC: COSV57199189; API