chr5-1294314-C-G

Position:

chr5-1294314-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_198253.3(TERT):c.572G>C(p.Ser191Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,591,576 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S191G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00095 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.505

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 -5 ACMG points.

PM1

In a region_of_interest GQ motif (size 139) in uniprot entity TERT_HUMAN there are 19 pathogenic changes around while only 7 benign (73%) in NM_198253.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006185025).

BP6

Variant 5-1294314-C-G is Benign according to our data. Variant chr5-1294314-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350804.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000945 (144/152370) while in subpopulation AFR AF= 0.00337 (140/41594). AF 95% confidence interval is 0.00291. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TERT	NM_198253.3 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant	2/15
TERT	NR_149162.3 linkuse as main transcript	n.651G>C		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3 linkuse as main transcript	n.651G>C		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant	2/16	1	NM_198253.3	P2	O14746-1
TERT	ENST00000334602.10 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant	2/15	1		A2	O14746-3
TERT	ENST00000460137.6 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant, NMD_transcript_variant	2/13	1			O14746-4
TERT	ENST00000656021.1 linkuse as main transcript	c.572G>C	p.Ser191Thr	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

139

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000955

GnomAD3 exomes

AF:

0.000226

AC:

AN:

203766

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

113938

show subpopulations

Gnomad AFR exome

AF:

0.00336

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

167

AN:

1439206

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

715782

show subpopulations

Gnomad4 AFR exome

AF:

0.00403

Gnomad4 AMR exome

AF:

0.000183

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000472

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000945

AC:

144

AN:

152370

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00337

Gnomad4 AMR

AF:

0.000131

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:

0.000945

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.00118

ESP6500AA

AF:

0.00243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000188

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 23, 2018	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 25, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 11, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 29, 2020

- -

Aplastic anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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 29, 2024

- -

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

Dyskeratosis congenita, autosomal dominant 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

TERT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Acute myeloid leukemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.24

DANN

Benign

0.31

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.40

T;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.0062

T;T

MetaSVM

Uncertain

0.0016

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.25

Sift

Benign

0.72

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.084

B;B

Vest4

0.093

MVP

0.74

MPC

0.99

ClinPred

0.0012

GERP RS

0.93

Varity_R

0.047

gMVP

0.55

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