5-1253803-C-T

Position:

chr5-1253803-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_198253.3(TERT):c.3324G>A(p.Pro1108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,611,298 control chromosomes in the GnomAD database, including 513 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. P1108P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 43 hom., cov: 33)

Exomes 𝑓: 0.023 ( 470 hom. )

Consequence

TERT
NM_198253.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -4.79

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:

(HGNC:):

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=-0.83).

BP6

Variant 5-1253803-C-T is Benign according to our data. Variant chr5-1253803-C-T is described in ClinVar as [Benign]. Clinvar id is 165375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1253803-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2723/152330) while in subpopulation NFE AF= 0.0267 (1813/68022). AF 95% confidence interval is 0.0256. There are 43 homozygotes in gnomad4. There are 1333 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TERT	NM_198253.3 linkuse as main transcript	c.3324G>A	p.Pro1108=	synonymous_variant	16/16	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.3135G>A	p.Pro1045=	synonymous_variant	15/15
TERT	NR_149162.3 linkuse as main transcript	n.3032G>A		non_coding_transcript_exon_variant	13/13
TERT	NR_149163.3 linkuse as main transcript	n.2996G>A		non_coding_transcript_exon_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.3324G>A	p.Pro1108=	synonymous_variant	16/16	1	NM_198253.3	P2	O14746-1
	ENST00000666708.1 linkuse as main transcript	n.289-871C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2722

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00388

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0176

AC:

4264

AN:

241596

Hom.:

AF XY:

0.0168

AC XY:

2206

AN XY:

131472

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00423

Gnomad EAS exome

AF:

0.000339

Gnomad SAS exome

AF:

0.00269

Gnomad FIN exome

AF:

0.0564

Gnomad NFE exome

AF:

0.0247

Gnomad OTH exome

AF:

0.0164

GnomAD4 exome

AF:

0.0227

AC:

33089

AN:

1458968

Hom.:

470

Cov.:

AF XY:

0.0223

AC XY:

16159

AN XY:

725546

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.00409

Gnomad4 ASJ exome

AF:

0.00494

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00240

Gnomad4 FIN exome

AF:

0.0553

Gnomad4 NFE exome

AF:

0.0257

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0179

AC:

2723

AN:

152330

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1333

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00387

Gnomad4 AMR

AF:

0.00555

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0529

Gnomad4 NFE

AF:

0.0267

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0215

Hom.:

Bravo

AF:

0.0136

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Pro1108Pro in exon 16 of TERT: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.4% (208/8522) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35033501). -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:2

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 29, 2023	- -

Aplastic anemia

Benign:1

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

- -

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Dyskeratosis congenita

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.085

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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