rs372272356

Positions:

chr5-1279464-G-A

Variant summary

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

The NM_198253.3(TERT):c.1957C>T(p.Arg653Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,549,108 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.707

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=0.100023955).

BP6

Variant 5-1279464-G-A is Benign according to our data. Variant chr5-1279464-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.1957C>T	p.Arg653Cys	missense_variant	5/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.1957C>T	p.Arg653Cys	missense_variant	5/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.2036C>T		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3 linkuse as main transcript	n.2036C>T		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.1957C>T	p.Arg653Cys	missense_variant	5/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000671

AC:

AN:

149072

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

80184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000183

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.000261

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.0000258

AC:

AN:

1396918

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

689086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.000140

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.0000835

Gnomad4 NFE exome

AF:

0.0000213

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000331

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000105

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.10

T;T

MetaSVM

Uncertain

-0.014

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.28

Sift

Benign

0.19

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.023

B;B

Vest4

0.28

MVP

0.41

MPC

1.4

ClinPred

0.039

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.099

gMVP

0.75

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