rs2736100

Positions:

• chr5-1286401-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_198253.3(TERT):​c.1574-3777G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 151,908 control chromosomes in the GnomAD database, including 20,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.52 (20520 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1 O:3
• Conservation: PhyloP100: -1.13

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-1286401-C-A is Benign according to our data. Variant chr5-1286401-C-A is described in ClinVar as [Benign]. Clinvar id is 375480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1574-3777G>T		intron_variant		ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1574-3777G>T		intron_variant			NP_001180305.1
TERT	NR_149162.3	n.1653-3777G>T		intron_variant, non_coding_transcript_variant
TERT	NR_149163.3	n.1653-3777G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1574-3777G>T		intron_variant		1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.1574-3777G>T		intron_variant		1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.1574-3777G>T		intron_variant, NMD_transcript_variant		1		ENSP00000425003
TERT	ENST00000656021.1	c.*883G>T		3_prime_UTR_variant, NMD_transcript_variant	3/17			ENSP00000499759

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78709 AN: 151790 Hom.: 20496 Cov.: 31

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.519 AC: 78771 AN: 151908 Hom.: 20520 Cov.: 31 AF XY: 0.521 AC XY: 38654 AN XY: 74238

Gnomad4 AFR AF: 0.539

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.411

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.492

Alfa AF: 0.494 Hom.: 34252

Bravo AF: 0.528

Asia WGS AF: 0.469 AC: 1632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1 Other:3

Revision: criteria provided, single submitter

Submissions by phenotype

Chronic obstructive pulmonary disease Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

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

- -

Interstitial lung disease 2 Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

Chronic osteomyelitis Other:1

association, no assertion criteria provided

case-control

Department of Orthopeadics and Traumatology, Nanfang Hospital

Sep 01, 2016

- -

Combined pulmonary fibrosis-emphysema syndrome Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.050
DANN	Benign	0.33

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: rs2736100; hg19: chr5-1286516; COSMIC: COSV57244861; COSMIC: COSV57244861;