rs1060503009

Variant names:

• chr5-1268626-C-A
• rs1060503009
• NM_198253.3:c.2476G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1268626-C-A
• chr5-1268626-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198253.3(TERT):​c.2476G>T​(p.Val826Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.48

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2476G>T	p.Val826Phe	missense_variant	Exon 9 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2476G>T	p.Val826Phe	missense_variant	Exon 9 of 15		NP_001180305.1
TERT	NR_149162.3	n.2373G>T		non_coding_transcript_exon_variant	Exon 7 of 13
TERT	NR_149163.3	n.2337G>T		non_coding_transcript_exon_variant	Exon 7 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2476G>T	p.Val826Phe	missense_variant	Exon 9 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459326 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725712

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: 0.00

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 826 of the TERT protein (p.Val826Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myelodysplastic syndrome and acute myeloid leukemia (PMID: 34019641). ClinVar contains an entry for this variant (Variation ID: 838619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TERT protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 34019641). 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. -

Dyskeratosis congenita Uncertain:1

Oct 06, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V826F variant (also known as c.2476G>T), located in coding exon 9 of the TERT gene, results from a G to T substitution at nucleotide position 2476. The valine at codon 826 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.070	T;T
Sift4G	Uncertain	0.023	D;D
Polyphen		0.99	D;P
Vest4		0.40
MutPred		0.34		Loss of methylation at K823 (P = 0.1604);Loss of methylation at K823 (P = 0.1604);
MVP		0.74
MPC		2.2
ClinPred		0.67	D
GERP RS		-0.85
Varity_R		0.074
gMVP		0.74

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: rs1060503009; hg19: chr5-1268741;