chr5-1293971-C-T

Position:

chr5-1293971-C-T

Variant summary

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

The ENST00000310581.10(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
ENST00000310581.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O: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]

TERT links:

Genome browser will be placed here

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	Protein
TERT	NM_198253.3 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant	2/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.994G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 linkuse as main transcript	n.994G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant	2/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant	2/15	1		ENSP00000334346	A2	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant, NMD_transcript_variant	2/13	1		ENSP00000425003		O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	c.915G>A	p.Ala305=	synonymous_variant, NMD_transcript_variant	2/17			ENSP00000499759

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

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.:

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.:

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:18Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2023	- -

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:1Other: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

Labcorp Genetics (formerly Invitae), Labcorp

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over