chr5-1294308-G-A

Position:

• chr5-1294308-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000310581.10(TERT):​c.578C>T​(p.Pro193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. P193S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT ENST00000310581.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.178

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.

• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.06801537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.578C>T	p.Pro193Leu	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.578C>T	p.Pro193Leu	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.657C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.657C>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.578C>T	p.Pro193Leu	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2
TERT	ENST00000334602.10	c.578C>T	p.Pro193Leu	missense_variant	2/15	1		ENSP00000334346	A2
TERT	ENST00000460137.6	c.578C>T	p.Pro193Leu	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003
TERT	ENST00000656021.1	c.578C>T	p.Pro193Leu	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000487 AC: 1 AN: 205140 Hom.: 0 AF XY: 0.00000872 AC XY: 1 AN XY: 114712

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: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000852 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Apr 09, 2023

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TERT function (PMID: 28677271). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TERT protein function. ClinVar contains an entry for this variant (Variation ID: 268079). This variant has not been reported in the literature in individuals affected with TERT-related conditions. 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 sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 193 of the TERT protein (p.Pro193Leu). -

Hepatocellular carcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan

Jun 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	3.0
DANN	Benign	0.82
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.061	T;T
Polyphen		0.0	B;B
Vest4		0.072
MutPred		0.24		Loss of glycosylation at P193 (P = 0.0094);Loss of glycosylation at P193 (P = 0.0094);
MVP		0.31
MPC		1.1
ClinPred		0.083	T
GERP RS		-3.5
Varity_R		0.046
gMVP		0.62

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: rs751762765; hg19: chr5-1294423;