rs943176303

Positions:

chr5-1294267-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_198253.3(TERT):c.619G>A(p.Val207Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,593,006 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.39

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 Uncertain_significance. Variant got 2 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=0.07738575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.619G>A	p.Val207Ile	missense_variant	2/16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.619G>A	p.Val207Ile	missense_variant	2/15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.698G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 link	n.698G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TERT	ENST00000310581.10 link	c.619G>A	p.Val207Ile	missense_variant	2/16	1	NM_198253.3	ENSP00000309572.5	O14746-1
TERT	ENST00000334602.10 link	c.619G>A	p.Val207Ile	missense_variant	2/15	1		ENSP00000334346.6	O14746-3
TERT	ENST00000460137.6 link	n.619G>A		non_coding_transcript_exon_variant	2/13	1		ENSP00000425003.1	O14746-4
TERT	ENST00000656021.1 link	n.619G>A		non_coding_transcript_exon_variant	2/17			ENSP00000499759.1	A0A590UK92

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000965

AC:

AN:

207352

Hom.:

AF XY:

0.00000862

AC XY:

AN XY:

115946

show subpopulations

Gnomad AFR exome

AF:

0.000167

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1440792

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716694

show subpopulations

Gnomad4 AFR exome

AF:

0.0000901

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

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:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 09, 2022

DNA sequence analysis of the TERT gene demonstrated a sequence change, c.619G>A, in exon 2 that results in an amino acid change, p.Val207Ile. This sequence change has been previously described in an individual with myelodysplastic syndrome with normal telomeres (PMID: 30523342). This sequence change has been described in the gnomAD database in two individuals which corresponds to a population frequency of 0.017% (dbSNP rs943176303). The p.Val207Ile change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is not known to be functional. The p.Val207Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val207Ile change remains unknown at this time. -

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 17, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 207 of the TERT protein (p.Val207Ile). 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 missense change has been observed in individual(s) with myelodysplastic syndrome (PMID: 30523342). ClinVar contains an entry for this variant (Variation ID: 471898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2024

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with myelodysplastic syndrome (MDS) (PMID: 30523342); This variant is associated with the following publications: (PMID: 30523342) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.6

DANN

Benign

0.86

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.077

T;T

MetaSVM

Uncertain

-0.016

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.14

Sift

Benign

0.41

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.12

B;B

Vest4

0.086

MutPred

0.30

Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);

MVP

0.60

MPC

0.88

ClinPred

0.041

GERP RS

-1.5

Varity_R

0.023

gMVP

0.60

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