5-1268585-C-T

Position:

• chr5-1268585-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_198253.3(TERT):​c.2517G>A​(p.Thr839Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,613,422 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (14 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.36

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP6: Variant 5-1268585-C-T is Benign according to our data. Variant chr5-1268585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1268585-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00194 (295/152358) while in subpopulation SAS AF= 0.0058 (28/4828). AF 95% confidence interval is 0.00412. There are 2 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2517G>A	p.Thr839Thr	synonymous_variant	9/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2517G>A	p.Thr839Thr	synonymous_variant	9/15		NP_001180305.1
TERT	NR_149162.3	n.2414G>A		non_coding_transcript_exon_variant	7/13
TERT	NR_149163.3	n.2378G>A		non_coding_transcript_exon_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2517G>A	p.Thr839Thr	synonymous_variant	9/16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00282 AC: 706 AN: 250212 Hom.: 2 AF XY: 0.00314 AC XY: 426 AN XY: 135582

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00237 AC: 3460 AN: 1461064 Hom.: 14 Cov.: 31 AF XY: 0.00253 AC XY: 1841 AN XY: 726792

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00786

Gnomad4 FIN exome AF: 0.00593

Gnomad4 NFE exome AF: 0.00182

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.00221 AC XY: 165 AN XY: 74496

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00715

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00134

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TERT: BP4, BP7 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2015	- -

Dyskeratosis congenita, autosomal dominant 2 Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 25, 2019	- -

Dyskeratosis congenita Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 21, 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. -

Aplastic anemia Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

Jan 30, 2024

- -

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

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. -

Acute myeloid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	0.12
CADD	Benign	0.15
DANN	Benign	0.95

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: rs140124989; hg19: chr5-1268700; COSMIC: COSV104395555; COSMIC: COSV104395555;