chr5-1253629-G-A

Variant names:

• chr5-1253629-G-A
• rs2853690
• NM_198253.3:c.*99C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198253.3(TERT):​c.*99C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 998,776 control chromosomes in the GnomAD database, including 16,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3360 hom., cov: 33)
  • Exomes 𝑓: 0.16 (12833 hom.)
• Consequence: TERT NM_198253.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.49

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]

ENSG00000287486 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-1253629-G-A is Benign according to our data. Variant chr5-1253629-G-A is described in ClinVar as [Benign]. Clinvar id is 350515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.*99C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.*99C>T		3_prime_UTR_variant	Exon 15 of 15		NP_001180305.1
TERT	NR_149162.3	n.3206C>T		non_coding_transcript_exon_variant	Exon 13 of 13
TERT	NR_149163.3	n.3170C>T		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581	c.*99C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29371 AN: 152112 Hom.: 3357 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.0849

Gnomad FIN AF: 0.0902

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.162 AC: 137406 AN: 846546 Hom.: 12833 Cov.: 11 AF XY: 0.158 AC XY: 69096 AN XY: 437754

Gnomad4 AFR exome AF: 0.314 AC: 6857 AN: 21860

Gnomad4 AMR exome AF: 0.0989 AC: 3459 AN: 34966

Gnomad4 ASJ exome AF: 0.128 AC: 2756 AN: 21480

Gnomad4 EAS exome AF: 0.00160 AC: 55 AN: 34304

Gnomad4 SAS exome AF: 0.0870 AC: 5967 AN: 68614

Gnomad4 FIN exome AF: 0.0977 AC: 3782 AN: 38714

Gnomad4 NFE exome AF: 0.184 AC: 107503 AN: 583446

Gnomad4 Remaining exome AF: 0.165 AC: 6591 AN: 40064

GnomAD4 genome AF: 0.193 AC: 29409 AN: 152230 Hom.: 3360 Cov.: 33 AF XY: 0.186 AC XY: 13858 AN XY: 74432

Gnomad4 AFR AF: 0.303 AC: 0.302799 AN: 0.302799

Gnomad4 AMR AF: 0.140 AC: 0.140233 AN: 0.140233

Gnomad4 ASJ AF: 0.127 AC: 0.127089 AN: 0.127089

Gnomad4 EAS AF: 0.00366 AC: 0.00365948 AN: 0.00365948

Gnomad4 SAS AF: 0.0857 AC: 0.0857498 AN: 0.0857498

Gnomad4 FIN AF: 0.0902 AC: 0.0902072 AN: 0.0902072

Gnomad4 NFE AF: 0.181 AC: 0.180988 AN: 0.180988

Gnomad4 OTH AF: 0.178 AC: 0.177862 AN: 0.177862

Alfa AF: 0.180 Hom.: 3855

Bravo AF: 0.202

Asia WGS AF: 0.0560 AC: 197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Aplastic anemia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Dyskeratosis congenita, autosomal dominant 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.18
DANN	Benign	0.54
Mutation Taster		=100/0	polymorphism (auto)

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: rs2853690; hg19: chr5-1253744;