5-1293748-G-A

Position:

chr5-1293748-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198253.3(TERT):c.1138C>T(p.Pro380Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,562,232 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00041 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.240

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077765286).

BP6

Variant 5-1293748-G-A is Benign according to our data. Variant chr5-1293748-G-A is described in ClinVar as [Benign]. Clinvar id is 242211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1293748-G-A is described in Lovd as [Likely_benign]. Variant chr5-1293748-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000407 (62/152366) while in subpopulation EAS AF= 0.00946 (49/5182). AF 95% confidence interval is 0.00735. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.1138C>T	p.Pro380Ser	missense_variant	2/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.1138C>T	p.Pro380Ser	missense_variant	2/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.1217C>T		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 linkuse as main transcript	n.1217C>T		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.1138C>T	p.Pro380Ser	missense_variant	2/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.1138C>T	p.Pro380Ser	missense_variant	2/15	1		ENSP00000334346	A2	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	c.1138C>T	p.Pro380Ser	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000425003		O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	c.1138C>T	p.Pro380Ser	missense_variant, NMD_transcript_variant	2/17			ENSP00000499759

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152248

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:

0.00924

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000808

AC:

135

AN:

167074

Hom.:

AF XY:

0.000865

AC XY:

AN XY:

89020

show subpopulations

Gnomad AFR exome

AF:

0.000105

Gnomad AMR exome

AF:

0.0000393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00997

Gnomad SAS exome

AF:

0.000255

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000160

AC:

226

AN:

1409866

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

133

AN XY:

696318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00379

Gnomad4 SAS exome

AF:

0.000537

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000184

Gnomad4 OTH exome

AF:

0.000667

GnomAD4 genome

AF:

0.000407

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00946

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000228

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.000555

AC:

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TERT: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dyskeratosis congenita

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 23, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 26, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 11, 2021

- -

Interstitial lung disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0078

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.20

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.061

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.010

B;B

Vest4

0.53

MVP

0.97

MPC

1.1

ClinPred

0.0063

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.045

gMVP

0.42

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