rs199422297

Positions:

chr5-1279311-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_198253.3(TERT):c.2110C>T(p.Pro704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000884 in 1,584,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

TERT
NM_198253.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.575

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 5-1279311-G-A is Pathogenic according to our data. Variant chr5-1279311-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1279311-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TERT	NM_198253.3 linkuse as main transcript	c.2110C>T	p.Pro704Ser	missense_variant	5/16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 linkuse as main transcript	c.2110C>T	p.Pro704Ser	missense_variant	5/15		NP_001180305.1
TERT	NR_149162.3 linkuse as main transcript	n.2189C>T		non_coding_transcript_exon_variant	5/13
TERT	NR_149163.3 linkuse as main transcript	n.2189C>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.2110C>T	p.Pro704Ser	missense_variant	5/16	1	NM_198253.3	ENSP00000309572	P2	O14746-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000507

AC:

AN:

197100

Hom.:

AF XY:

0.00

AC XY:

AN XY:

107652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000489

AC:

AN:

1431824

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

709724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000637

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000897

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2022	Observed in individuals with TERT-related disorders in published literature (Du 2009, Batista 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30523342, 23901009, 18042801, 18635888, 23538340, 18931339, 27418648, 21602826, 28099038) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2022	The c.2110C>T sequence change in exon 5 results in an amino acid change, p.Pro704Ser. The p.Pro704Ser change affects a poorly 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.Pro704Ser substitution. This sequence change has been reported in the homozygous state in two individuals with dyskeratosis congenital (PMID: 18042801, 18931339). It has also been described in the heterozygous state in three individuals from one family with pulmonary fibrosis and one individual with aplastic anemia (PMID: 1863588, 18931339). Multiple studies have found that the p.Pro704Ser change results in reduced telomerase activity (PMID: 18042801, 23901009. 18931339). This sequence change has been described in the gnomAD database in 2 individuals which corresponds to a population frequency of 0.0009% (dbSNP rs199422297). Based on these evidences this sequence change is classified as likely pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 704 of the TERT protein (p.Pro704Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of TERT-related conditions (PMID: 18042801, 18635888, 18931339, 21602826, 27418648, 30523342; Invitae). ClinVar contains an entry for this variant (Variation ID: 39108). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 18042801, 21602826, 23901009, 25365545). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Pulmonary fibrosis

Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Jun 09, 2022

Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted -

Dyskeratosis congenita, autosomal dominant 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 09, 2024

- -

Autosomal recessive dyskeratosis congenita 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2008

- -

Dyskeratosis congenita

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The p.P704S pathogenic mutation (also known as c.2110C>T), located in coding exon 5 of the TERT gene, results from a C to T substitution at nucleotide position 2110. The proline at codon 704 is replaced by serine, an amino acid with similar properties. This mutation has demonstrated both an autosomal recessive inheritance presenting with a more severe phenotype as well as autosomal dominant inheritance with variable presentation, age of onset, and reduced penetrance. This alteration was first reported in homozygous state in a proband diagnosed with dyskeratosis congenita and additional abnormalities; one parent who was compound heterozygous with another alteration had shortened telomeres, while the other heterozygous parent was asymptomatic in the 6th decade of life. Functional analysis in this study demonstrated that this mutation severely reduced telomerase activity to 13% of wild type (Du HY et al. Blood, 2008 Feb;111:1128-30). This mutation was also identified in the heterozygous state in three siblings with pulmonary fibrosis, and other unrelated individuals with myelodysplastic syndrome and/or pulmonary fibrosis (Cronkhite JT et al. Am. J. Respir. Crit. Care Med., 2008 Oct;178:729-37; Keel SB et al. Haematologica, 2016 11;101:1343-1350; Gutierrez-Rodrigues F et al. Genet Med, 2019 07;21:1594-1602). Additional in vitro functional studies demonstrated that this mutation significantly reduces activity and processivity of telomerase (Batista LF et al. Nature, 2011 Jun;474:399-402; Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dyskeratosis congenita, autosomal dominant 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.74

T;T

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

2.1e-8

A;A;A;A

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.62

Sift

Benign

0.046

D;D

Sift4G

Benign

0.27

T;T

Polyphen

1.0

D;B

Vest4

0.41

MutPred

0.74

Gain of relative solvent accessibility (P = 0.0507);Gain of relative solvent accessibility (P = 0.0507);

MVP

0.95

MPC

1.3

ClinPred

0.17

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.88

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