rs1060503002

chr5-1293324-C-Achr5-1293324-C-T

Variant summary

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

The NM_198253.3(TERT):c.1562G>T(p.Arg521Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R521C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.766

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/exons	MANE	UniProt
TERT	NM_198253.3	c.1562G>T	p.Arg521Leu	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1562G>T	p.Arg521Leu	missense_variant	2/15
TERT	NR_149162.3	n.1641G>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1641G>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1562G>T	p.Arg521Leu	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1562G>T	p.Arg521Leu	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.1562G>T	p.Arg521Leu	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1562G>T	p.Arg521Leu	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249340 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135332

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460658 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726650

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 521 of the TERT protein (p.Arg521Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 410675). 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. 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, autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 27, 2022

This TERT variant (rs1060503002) is rare (<0.1%) in a large population dataset (gnomAD: 1/249340 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar (Variation ID: 410675). It has not been reported in the literature in individuals with TERT-related conditions to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of TERT c.1562G>T to be uncertain at this time -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 27, 2022

This TERT variant (rs1060503002) is rare (<0.1%) in a large population dataset (gnomAD: 1/249340 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar (Variation ID: 410675). It has not been reported in the literature in individuals with TERT-related conditions to our knowledge. Two bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of TERT c.1562G>T to be uncertain at this time -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;P
Vest4		0.33
MutPred		0.56		Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);
MVP		0.78
MPC		2.2
ClinPred		0.94	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503002; hg19: chr5-1293439;