5-1294213-C-G

Variant names:

• chr5-1294213-C-G
• rs1060502999
• NM_198253.3:c.673G>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_198253.3(TERT):​c.673G>C​(p.Gly225Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.16

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_benign. Variant got -1 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=0.06451115).
• BP6: Variant 5-1294213-C-G is Benign according to our data. Variant chr5-1294213-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410666.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.673G>C	p.Gly225Arg	missense_variant	Exon 2 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.673G>C	p.Gly225Arg	missense_variant	Exon 2 of 15		NP_001180305.1
TERT	NR_149162.3	n.752G>C		non_coding_transcript_exon_variant	Exon 2 of 13
TERT	NR_149163.3	n.752G>C		non_coding_transcript_exon_variant	Exon 2 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.673G>C	p.Gly225Arg	missense_variant	Exon 2 of 16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.673G>C	p.Gly225Arg	missense_variant	Exon 2 of 15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.673G>C		non_coding_transcript_exon_variant	Exon 2 of 13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.673G>C		non_coding_transcript_exon_variant	Exon 2 of 17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Apr 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not expected to disrupt TERT protein function. ClinVar contains an entry for this variant (Variation ID: 410666). This variant has not been reported in the literature in individuals affected with TERT-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 225 of the TERT protein (p.Gly225Arg). -

Dyskeratosis congenita Benign:1

Feb 13, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	4.7
DANN	Benign	0.38
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.60	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-1.7	N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.21
Sift	Benign	0.54	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;B
Vest4		0.087
MutPred		0.25		Gain of methylation at G225 (P = 0.004);Gain of methylation at G225 (P = 0.004);
MVP		0.33
MPC		1.2
ClinPred		0.044	T
GERP RS		0.70
Varity_R		0.081
gMVP		0.47

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: rs1060502999; hg19: chr5-1294328; COSMIC: COSV57223154; COSMIC: COSV57223154;