5-1294846-G-A

Position:

• chr5-1294846-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_198253.3(TERT):​c.144C>T​(p.Arg48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000023 in 1,307,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TERT NM_198253.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.458

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=-0.458 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.144C>T	p.Arg48=	synonymous_variant	1/16	ENST00000310581.10
TERT	NM_001193376.3	c.144C>T	p.Arg48=	synonymous_variant	1/15
TERT	NR_149162.3	n.223C>T		non_coding_transcript_exon_variant	1/13
TERT	NR_149163.3	n.223C>T		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.144C>T	p.Arg48=	synonymous_variant	1/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.144C>T	p.Arg48=	synonymous_variant	1/15	1		A2
TERT	ENST00000460137.6	c.144C>T	p.Arg48=	synonymous_variant, NMD_transcript_variant	1/13	1
TERT	ENST00000656021.1	c.144C>T	p.Arg48=	synonymous_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000155 AC: 1 AN: 64456 Hom.: 0 AF XY: 0.0000269 AC XY: 1 AN XY: 37166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000795

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000230 AC: 3 AN: 1307094 Hom.: 0 Cov.: 34 AF XY: 0.00000311 AC XY: 2 AN XY: 642936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.56e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TERT-related disease. While this variant is present in population databases (rs746281705), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change affects codon 48 of the TERT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TERT protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.78

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: rs746281705; hg19: chr5-1294961;