5-1293991-C-T

Position:

chr5-1293991-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198253.3(TERT):c.895G>A(p.Val299Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000953 in 1,574,112 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 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.485

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:

TERT (HGNC:):

TERT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08668664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3 linkuse as main transcript	c.895G>A	p.Val299Met	missense_variant	2/16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 linkuse as main transcript	c.895G>A	p.Val299Met	missense_variant	2/15		NP_001180305.1	O14746-3
TERT	NR_149162.3 linkuse as main transcript	n.974G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 linkuse as main transcript	n.974G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.895G>A	p.Val299Met	missense_variant	2/16	1	NM_198253.3	ENSP00000309572.5	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.895G>A	p.Val299Met	missense_variant	2/15	1		ENSP00000334346.6	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	n.895G>A		non_coding_transcript_exon_variant	2/13	1		ENSP00000425003.1	O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	n.895G>A		non_coding_transcript_exon_variant	2/17			ENSP00000499759.1	A0A590UK92

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000377

AC:

AN:

185886

Hom.:

AF XY:

0.0000396

AC XY:

AN XY:

100920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000241

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000985

AC:

AN:

1421920

Hom.:

Cov.:

AF XY:

0.00000993

AC XY:

AN XY:

704628

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000250

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:

9.13e-7

Gnomad4 OTH exome

AF:

0.0000509

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000338

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign: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

Aug 12, 2021

- -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 30, 2024

The p.V299M variant (also known as c.895G>A), located in coding exon 2 of the TERT gene, results from a G to A substitution at nucleotide position 895. The valine at codon 299 is replaced by methionine, an amino acid with highly similar properties. This variant was reported as heterozygous in multiple individuals with features consistent with TERT-related disorder (Calado RT et al. Proc Natl Acad Sci U S A, 2009 Jan;106:1187-92; Mirabello L et al. JAMA Oncol, 2020 May;6:724-734). Functional studies suggest that the variant has no major effect on telomerase activity; however, additional evidence is needed to confirm these findings (Calado RT et al. Proc Natl Acad Sci U S A, 2009 Jan;106:1187-92; Zaug AJ et al. Nucleic Acids Res, 2013 Oct;41:8969-78). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

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 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.087

T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.0

L;L

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.34

N;N

REVEL

Benign

0.23

Sift

Benign

0.21

T;T

Sift4G

Benign

0.083

T;T

Polyphen

0.79

P;P

Vest4

0.13

MutPred

0.31

Gain of MoRF binding (P = 0.1634);Gain of MoRF binding (P = 0.1634);

MVP

0.56

MPC

1.3

ClinPred

0.066

GERP RS

-0.47

Varity_R

0.029

gMVP

0.21

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