rs200843534

Positions:

• chr5-1294483-C-G
• chr5-1294483-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_198253.3(TERT):​c.403G>C​(p.Gly135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,576 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: 7.0e-7 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.197

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]

TERT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest RNA-interacting domain 1 (size 229) in uniprot entity TERT_HUMAN there are 10 pathogenic changes around while only 3 benign (77%) in NM_198253.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3629657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.403G>C	p.Gly135Arg	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.403G>C	p.Gly135Arg	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.482G>C		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.482G>C		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.403G>C	p.Gly135Arg	missense_variant	2/16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.403G>C	p.Gly135Arg	missense_variant	2/15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.403G>C		non_coding_transcript_exon_variant	2/13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.403G>C		non_coding_transcript_exon_variant	2/17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000489 AC: 1 AN: 204316 Hom.: 0 AF XY: 0.00000876 AC XY: 1 AN XY: 114114

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: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436576 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 714138

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: 9.03e-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

Sep 03, 2021

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. 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. This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 135 of the TERT protein (p.Gly135Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.15	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.69	P;P
Vest4		0.16
MutPred		0.72		Gain of MoRF binding (P = 0.0055);Gain of MoRF binding (P = 0.0055);
MVP		0.77
MPC		1.3
ClinPred		0.22	T
GERP RS		2.8
Varity_R		0.095
gMVP		0.92

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: rs200843534; hg19: chr5-1294598;