5-1295234-A-G

Variant names:

• chr5-1295234-A-G
• rs2853669
• NM_198253.3:c.-245T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.-245T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 151,924 control chromosomes in the GnomAD database, including 5,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (5628 hom., cov: 34)
• Consequence: TERT NM_198253.3 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.887

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-1295234-A-G is Benign according to our data. Variant chr5-1295234-A-G is described in ClinVar as [Benign]. Clinvar id is 539240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.-245T>C		upstream_gene_variant		ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.-245T>C		upstream_gene_variant			NP_001180305.1
TERT	NR_149162.3	n.-166T>C		upstream_gene_variant
TERT	NR_149163.3	n.-166T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.-245T>C		upstream_gene_variant		1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.-245T>C		upstream_gene_variant		1		ENSP00000334346.6
TERT	ENST00000460137.6	n.-245T>C		upstream_gene_variant		1		ENSP00000425003.1
TERT	ENST00000656021.1	n.-245T>C		upstream_gene_variant				ENSP00000499759.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38580 AN: 151816 Hom.: 5623 Cov.: 34

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.284

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38593 AN: 151924 Hom.: 5628 Cov.: 34 AF XY: 0.255 AC XY: 18952 AN XY: 74272

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.367

Gnomad4 SAS AF: 0.529

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.293

Alfa AF: 0.266 Hom.: 1141

Bravo AF: 0.246

Asia WGS AF: 0.442 AC: 1523 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26298771, 26575952, 30610818, 31395865, 29534075, 25680408, 16737810, 23348503, 24101484) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Oct 31, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.9
DANN	Benign	0.064

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2853669; hg19: chr5-1295349; COSMIC: COSV57201510;