chr5-1293430-G-A

Position:

• chr5-1293430-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000310581.10(TERT):​c.1456C>T​(p.Arg486Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,056 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R486H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TERT ENST00000310581.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 5.58

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in ENST00000310581.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 5-1293430-G-A is Pathogenic according to our data. Variant chr5-1293430-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39101.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, not_provided=1}. Variant chr5-1293430-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1456C>T	p.Arg486Cys	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1456C>T	p.Arg486Cys	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.1535C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1535C>T		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.1456C>T	p.Arg486Cys	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.1456C>T	p.Arg486Cys	missense_variant	2/15	1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.1456C>T	p.Arg486Cys	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003
TERT	ENST00000656021.1	c.1456C>T	p.Arg486Cys	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460056 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pulmonary fibrosis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

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

Likely pathogenic, criteria provided, single submitter

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

May 19, 2022

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

TERT: PS4:Moderate, PM2:Supporting, PP1, PP4, PS3:Supporting -

Dyskeratosis congenita Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2016

The p.R486C variant (also known as c.1456C>T), located in coding exon 2 of the TERT gene, results from a C to T substitution at nucleotide position 1456. The arginine at codon 486 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in one individual with idiopathic pulmonary fibrosis. In addition, in vitro functional studies showed reduced telomerase activity and shortened telomeres (Tsakiri KD, Proc. Natl. Acad. Sci. U.S.A. 2007 May; 104(18):7552-7). This variant was previously reported in the SNPDatabase as rs199422293. This variant was not reported in population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6496 samples (12992 alleles) with coverage at this position.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2021

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 486 of the TERT protein (p.Arg486Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis (PMID: 17460043, 20502709, 27540018). ClinVar contains an entry for this variant (Variation ID: 39101). 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. -

Interstitial lung disease 2 Other:1

not provided, no classification provided

literature only

GeneReviews

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.46
MutPred		0.66		Loss of disorder (P = 0.0127);Loss of disorder (P = 0.0127);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.54
gMVP		0.57

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: rs199422293; hg19: chr5-1293545;