rs373400596

Positions:

chr5-1255294-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4BP6

The NM_198253.3(TERT):c.3150G>C(p.Lys1050Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K1050E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.0810

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:

ENSG00000287486 (HGNC:):

ENSG00000287486 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a region_of_interest CTE (size 196) in uniprot entity TERT_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_198253.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-1255296-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.32261068).

BP6

Variant 5-1255294-C-G is Benign according to our data. Variant chr5-1255294-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=6, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TERT	NM_198253.3 link	c.3150G>C	p.Lys1050Asn	missense_variant	14/16	ENST00000310581.10	NP_937983.2	O14746-1
TERT	NM_001193376.3 link	c.2961G>C	p.Lys987Asn	missense_variant	13/15		NP_001180305.1	O14746-3
TERT	NR_149162.3 link	n.2858G>C		non_coding_transcript_exon_variant	11/13
TERT	NR_149163.3 link	n.2822G>C		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.3150G>C	p.Lys1050Asn	missense_variant	14/16	1	NM_198253.3	ENSP00000309572.5		O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

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:

0.000478

GnomAD3 exomes

AF:

0.0000928

AC:

AN:

247956

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000602

AC:

AN:

1461490

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000473

AC:

ExAC

AF:

0.0000826

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dyskeratosis congenita, autosomal dominant 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 02, 2016	The TERT c.3150G>C (p.Lys1050Asn) missense variant has been identified by Collopy et al. (2015) in a homozygous state in one individual and his sister, both of whom have bone marrow failure and nail dystrophy. Both individuals also showed a shortened telomere length. The variant was shown to result in 56% of telomerase activity compared to wild type. The brother was also found to carry a heterozygous variant in the TERC gene which resulted in 4.7% telomerase activity. Control data are unavailable for the p.Lys1050Asn variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Lys1050Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for dyskeratosis congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 15, 2020

DNA sequence analysis of the TERT gene demonstrated a sequence change, c.3150G>C, in exon 14 that results in an amino acid change, p.Lys1050Asn. This sequence change has been reported in the gnomAD database with a frequency of 0.2% in the Ashkenazi Jewish sub-population (dbSNP rs373400596). The p.Lys1050Asn change affects a moderately conserved amino acid residue located in a domain of the TERT protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, Revel) provide contradictory results for the p.Lys1050Asn substitution. This sequence change has been described in the homozygous state in one individual with bone marrow failure, nail dystrophy, renal failure, and dental/skin abnormalities, in addition to a novel heterozygous sequence change in the TERC gene. This individual√¢‚Ç¨‚Ñ¢s sister with bone marrow failure and nail dystrophy was also found to be homozygous for this TERT variant, but did not carry the same variant in TERC (PMID: 26024875). Results of other first-degree relatives from this family were not reported. The p.Lys1050Asn change has been demonstrated to reduce telomerase activity compared with normal controls, however normal telomerase cutoffs have not been well established (PMID: 26024875). A different pathogenic sequence change affecting the same amino acid residue (p.Lys1050Glu) has been described in a patient with pulmonary fibrosis (PMID: 18635888). Due to the frequency of this sequence change in population databases, the p.Lys1050Asn is classified as a variant of unknown significance. -

Aplastic anemia

Uncertain:1

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2023

Published functional studies demonstrate intermediate telomerase activity (Collopy 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29758336, 27540018, 29463756, 26024875, 26158642, 28495916, 27354474, 29625052, 28104920, 31448843, 32526789) -

Dyskeratosis congenita

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jun 15, 2021

- -

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 28, 2025

- -

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

Benign:1

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.32

T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.57

Sift

Benign

0.037

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;P

Vest4

0.24

MutPred

0.65

Loss of ubiquitination at K1050 (P = 0.063);.;

MVP

0.94

MPC

1.4

ClinPred

0.21

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.32

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