chr5-1294378-C-T

Position:

• chr5-1294378-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000310581.10(TERT):​c.508G>A​(p.Val170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,426,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. V170L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: TERT ENST00000310581.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 0.708

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 5 ACMG points.

• PM1: In a region_of_interest GQ motif (size 139) in uniprot entity TERT_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in ENST00000310581.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.508G>A	p.Val170Met	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.508G>A	p.Val170Met	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.587G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.587G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.508G>A	p.Val170Met	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.508G>A	p.Val170Met	missense_variant	2/15	1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.508G>A	p.Val170Met	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003
TERT	ENST00000656021.1	c.508G>A	p.Val170Met	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000535 AC: 1 AN: 186834 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 104316

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000266 AC: 38 AN: 1426780 Hom.: 0 Cov.: 35 AF XY: 0.0000254 AC XY: 18 AN XY: 708630

Gnomad4 AFR exome AF: 0.0000302

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: 0.0000336

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ExAC AF: 0.00000868 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 26, 2011

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 170 of the TERT protein (p.Val170Met). This variant is present in population databases (rs387907248, gnomAD 0.001%). This missense change has been observed in individual(s) with aplastic anemia and pulmonary fibrosis (PMID: 21436073, 24833766, 35776903). ClinVar contains an entry for this variant (Variation ID: 36947). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 21436073). 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. -

Aplastic anemia;C0023467:Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9;C4551974:Dyskeratosis congenita, autosomal dominant 1;C5561926:Interstitial lung disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Dyskeratosis congenita, autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 22, 2023

- -

TERT-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2023

The TERT c.508G>A variant is predicted to result in the amino acid substitution p.Val170Met. This variant has been reported in several individuals with aplastic anaemia and pulmonary fibrosis (Parry et al. 2011. PubMed ID: 21436073; Silhan et al. 2014. PubMed ID: 24833766; Gutierrez-Rodrigues et al. 2018. PubMed ID: 30523342). Telomerase activity assay showed that this variant may decrease enzyme activity (Parry et al. 2011. PubMed ID: 21436073). This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1294493-C-T). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.98	D;D
Vest4		0.59
MutPred		0.29		Gain of glycosylation at P173 (P = 0.1645);Gain of glycosylation at P173 (P = 0.1645);
MVP		0.98
MPC		2.2
ClinPred		0.80	D
GERP RS		2.4
Varity_R		0.18
gMVP		0.93

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: rs387907248; hg19: chr5-1294493;