chr5-1293475-G-A

Position:

• chr5-1293475-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198253.3(TERT):​c.1411C>T​(p.Arg471Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,451,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.774

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30414748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3	c.1411C>T	p.Arg471Trp	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.1411C>T	p.Arg471Trp	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3	n.1490C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1490C>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.1411C>T	p.Arg471Trp	missense_variant	2/16	1	NM_198253.3	ENSP00000309572.5
TERT	ENST00000334602.10	c.1411C>T	p.Arg471Trp	missense_variant	2/15	1		ENSP00000334346.6
TERT	ENST00000460137.6	n.1411C>T		non_coding_transcript_exon_variant	2/13	1		ENSP00000425003.1
TERT	ENST00000656021.1	n.1411C>T		non_coding_transcript_exon_variant	2/17			ENSP00000499759.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1451230 Hom.: 0 Cov.: 32 AF XY: 0.00000693 AC XY: 5 AN XY: 721190

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

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

Oct 03, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 471 of the TERT protein (p.Arg471Trp). 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 variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 574952). 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. -

Dyskeratosis congenita, autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.23
Sift	Benign	0.050	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		0.58	P;B
Vest4		0.43
MVP		0.50
MPC		1.2
ClinPred		0.15	T
GERP RS		-0.84
Varity_R		0.35
gMVP		0.71

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: rs750721558; hg19: chr5-1293590; COSMIC: COSV99717981; COSMIC: COSV99717981;