5-1293493-C-G

Position:

chr5-1293493-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_198253.3(TERT):c.1393G>C(p.Val465Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,587,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.91

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.017994583).

BP6

Variant 5-1293493-C-G is Benign according to our data. Variant chr5-1293493-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539202.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.1472G>C		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 linkuse as main transcript	n.1472G>C		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant	2/15	1		ENSP00000334346	A2	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003		O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	c.1393G>C	p.Val465Leu	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

196768

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

106920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00148

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1435296

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

711926

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000392

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000672

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; Reported as n.1451G>C, observed in a bone marrow sample in an individual with acute myeloid leukemia (PMID: 23157242); This variant is associated with the following publications: (PMID: 26298771, 23157242) -

TERT-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2023

The TERT c.1393G>C variant is predicted to result in the amino acid substitution p.Val465Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1293608-C-G). It has conflicting interpretations in ClinVar of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/539202/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.1

DANN

Benign

0.16

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-0.86

N;N

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.19

N;N

REVEL

Benign

0.20

Sift

Benign

0.55

T;T

Sift4G

Benign

0.97

T;T

Polyphen

0.012

B;B

Vest4

0.13

MutPred

0.47

Loss of phosphorylation at Y462 (P = 0.1464);Loss of phosphorylation at Y462 (P = 0.1464);

MVP

0.69

MPC

1.1

ClinPred

0.012

GERP RS

1.0

Varity_R

0.12

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over