NM_198253.3:c.1770-377C>G

Variant names:

• chr5-1280715-G-C
• rs4975538
• NM_198253.3:c.1770-377C>G

Variant summary

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

The NM_198253.3(TERT):​c.1770-377C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,124 control chromosomes in the GnomAD database, including 7,862 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 0.31 (7862 hom., cov: 34)
• Consequence: TERT NM_198253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.1770-377C>G		intron_variant	Intron 3 of 15	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1770-377C>G		intron_variant	Intron 3 of 14		NP_001180305.1
TERT	NR_149162.3	n.1849-377C>G		intron_variant	Intron 3 of 12
TERT	NR_149163.3	n.1849-377C>G		intron_variant	Intron 3 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1770-377C>G		intron_variant	Intron 3 of 15	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47547 AN: 152008 Hom.: 7860 Cov.: 34

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.359

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

GnomAD4 genome AF: 0.313 AC: 47559 AN: 152124 Hom.: 7862 Cov.: 34 AF XY: 0.313 AC XY: 23246 AN XY: 74362

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.368

Alfa AF: 0.223 Hom.: 566

Bravo AF: 0.299

Asia WGS AF: 0.403 AC: 1402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.67

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: rs4975538; hg19: chr5-1280830;