rs2736098

chr5-1293971-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:3
• Conservation: PhyloP100: -1.61

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]

ACMG classification

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
TERT	NM_198253.3	c.915G>A	p.Ala305=	synonymous_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.915G>A	p.Ala305=	synonymous_variant	2/15
TERT	NR_149162.3	n.994G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.994G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.915G>A	p.Ala305=	synonymous_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.915G>A	p.Ala305=	synonymous_variant	2/15	1		A2
TERT	ENST00000460137.6	c.915G>A	p.Ala305=	synonymous_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.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

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

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

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

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:17 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, 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. -

Dyskeratosis congenita, autosomal dominant 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Aplastic anemia Benign:1 Other:1

not provided, no classification provided	literature only	Radiation Cancer Biology Lab, University of Rajasthan Jaipur	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 28, 2022

- -

Dyskeratosis congenita Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2014

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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Dyskeratosis congenita, autosomal dominant 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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

Other links and lift over

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