rs199422297

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_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 (★★). Synonymous variant affecting the same amino acid position (i.e. P704P) has been classified as Likely benign.

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:8O:1

Conservation

PhyloP100: 0.575

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
dyskeratosis congenita, autosomal dominant 2
Inheritance: AR, AD, SD, Unknown Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
acute myeloid leukemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma, cutaneous malignant, susceptibility to, 9
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TERT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_198253.3

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 39108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TERT	NM_198253.3 link	c.2110C>T	p.Pro704Ser	missense_variant	Exon 5 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3 link	c.2110C>T	p.Pro704Ser	missense_variant	Exon 5 of 15		NP_001180305.1
TERT	NR_149162.3 link	n.2189C>T		non_coding_transcript_exon_variant	Exon 5 of 13
TERT	NR_149163.3 link	n.2189C>T		non_coding_transcript_exon_variant	Exon 5 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10 link	c.2110C>T	p.Pro704Ser	missense_variant	Exon 5 of 16	1	NM_198253.3	ENSP00000309572.5

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

GnomAD2 exomes

AF:

0.00000507

AC:

AN:

197100

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

32866

American (AMR)

AF:

0.00

AC:

AN:

40418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

38188

South Asian (SAS)

AF:

0.00

AC:

AN:

81970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00000637

AC:

AN:

1099468

Other (OTH)

AF:

0.00

AC:

AN:

59162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000897

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 22, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Oct 14, 2022

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jul 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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

Jun 09, 2022

Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center

Significance:Likely risk allele

Review Status:no assertion criteria provided

Collection Method:research

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

Dyskeratosis congenita, autosomal dominant 2

Pathogenic:1

Mar 09, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive dyskeratosis congenita 4

Pathogenic:1

Feb 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dyskeratosis congenita

Pathogenic:1

Sep 16, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

TERT-related disorder

Pathogenic:1

Oct 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TERT c.2110C>T (p.Pro704Ser) results in a non-conservative amino acid change located in the Reverse transcriptase domain (IPR000477) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-06 in 197100 control chromosomes (gnomAD). The variant, c.2110C>T, has been reported in the literature in a homozygous individual affected with Dyskeratosis Congenita (Du_2008), and in multiple heterozygous individuals affected with TERT-Related Disorders, including (familial) pulmonary fibrosis and osteoporosis (Du_2008, Cronkhite_2008, Newton_2016, Gutierrez-Rodrigues_2019), but was also found in heterozygous unaffected family members (Du_2008), indicating variable penetrance. These data indicate that the variant is very likely to be associated with disease; of note, decreased telomere length was found in several affected individuals. Multiple publications reported experimental evidence evaluating an impact on protein function, and all demonstrated severely reduced activity (e.g. Du_2008, Batista_2011, Zaug_2013); the most pronounced variant effect results in 1-13% of normal activity. ClinVar contains an entry for this variant (Variation ID: 39108). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dyskeratosis congenita, autosomal dominant 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

0.57

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

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over