rs4975605

Positions:

• chr5-1275413-C-A

Variant summary

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

The NM_198253.3(TERT):​c.2287-3133G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 149,290 control chromosomes in the GnomAD database, including 13,504 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 0.42 (13504 hom., cov: 29)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.2287-3133G>T		intron_variant		ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2287-3133G>T		intron_variant			NP_001180305.1
TERT	NR_149162.3	n.2365+3228G>T		intron_variant, non_coding_transcript_variant
TERT	NR_149163.3	n.2329+3228G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2287-3133G>T		intron_variant		1	NM_198253.3	ENSP00000309572	P2

Frequencies

GnomAD3 genomes AF: 0.419 AC: 62579 AN: 149184 Hom.: 13503 Cov.: 29

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.419 AC: 62596 AN: 149290 Hom.: 13504 Cov.: 29 AF XY: 0.408 AC XY: 29793 AN XY: 72944

Gnomad4 AFR AF: 0.426

Gnomad4 AMR AF: 0.343

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.466

Gnomad4 OTH AF: 0.413

Alfa AF: 0.448 Hom.: 9749

Bravo AF: 0.424

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.30

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: rs4975605; hg19: chr5-1275528;