rs2736099

chr5-1287225-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198253.3(TERT):c.1574-4601T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,012 control chromosomes in the GnomAD database, including 38,154 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (38154 hom., cov: 31)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1574-4601T>C		intron_variant		ENST00000310581.10
TERT	NM_001193376.3	c.1574-4601T>C		intron_variant
TERT	NR_149162.3	n.1653-4601T>C		intron_variant, non_coding_transcript_variant
TERT	NR_149163.3	n.1653-4601T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1574-4601T>C		intron_variant		1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1574-4601T>C		intron_variant		1		A2
TERT	ENST00000460137.6	c.1574-4601T>C		intron_variant, NMD_transcript_variant		1
TERT	ENST00000656021.1	c.*198-139T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106725 AN: 151894 Hom.: 38100 Cov.: 31

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.703 AC: 106836 AN: 152012 Hom.: 38154 Cov.: 31 AF XY: 0.700 AC XY: 52032 AN XY: 74280

Gnomad4 AFR AF: 0.831

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.599

Gnomad4 EAS AF: 0.570

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.651

Gnomad4 OTH AF: 0.652

Alfa AF: 0.659 Hom.: 10546

Bravo AF: 0.714

Asia WGS AF: 0.548 AC: 1910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.6
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: rs2736099; hg19: chr5-1287340;