5-1280171-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_198253.3(TERT):c.1937G>A(p.Arg646His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,004 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R646C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.649

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07924053).

BP6

Variant 5-1280171-C-T is Benign according to our data. Variant chr5-1280171-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471838.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr5-1280171-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TERT	NM_198253.3 linkuse as main transcript	c.1937G>A	p.Arg646His	missense_variant	4/16	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.1937G>A	p.Arg646His	missense_variant	4/15
TERT	NR_149162.3 linkuse as main transcript	n.2016G>A		non_coding_transcript_exon_variant	4/13
TERT	NR_149163.3 linkuse as main transcript	n.2016G>A		non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.1937G>A	p.Arg646His	missense_variant	4/16	1	NM_198253.3	P2	O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000119

AC:

AN:

251338

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The p.R646H variant (also known as c.1937G>A), located in coding exon 4 of the TERT gene, results from a G to A substitution at nucleotide position 1937. The arginine at codon 646 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

Cadd

Benign

7.9

Dann

Benign

0.96

DEOGEN2

Uncertain

0.51

D;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.079

T;T

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

0.83

L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.41

N;N

REVEL

Benign

0.14

Sift

Benign

0.15

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0060

B;B

Vest4

0.085

MutPred

0.45

Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);

MVP

0.57

MPC

1.3

ClinPred

0.037

GERP RS

-2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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