rs199422298

Variant names:

• chr5-1278780-G-A
• rs199422298
• NM_198253.3:c.2147C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-1278780-G-A
• chr5-1278780-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_198253.3(TERT):​c.2147C>T​(p.Ala716Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,756 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A716T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 5.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a turn (size 4) in uniprot entity TERT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr5-1278781-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 5-1278780-G-A is Pathogenic according to our data. Variant chr5-1278780-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-1278780-G-A is described in Lovd as [Pathogenic]. Variant chr5-1278780-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TERT	NM_198253.3	c.2147C>T	p.Ala716Val	missense_variant	Exon 6 of 16	ENST00000310581.10	NP_937983.2
TERT	NM_001193376.3	c.2147C>T	p.Ala716Val	missense_variant	Exon 6 of 15		NP_001180305.1
TERT	NR_149162.3	n.2226C>T		non_coding_transcript_exon_variant	Exon 6 of 13
TERT	NR_149163.3	n.2210-20C>T		intron_variant	Intron 5 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TERT	ENST00000310581.10	c.2147C>T	p.Ala716Val	missense_variant	Exon 6 of 16	1	NM_198253.3	ENSP00000309572.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced telomerase activity and telomere length (Du 2009, Vulliamy 2011); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29596117, 18931339, 21931702, 23618685, 29146883, 20301779, 23538340) -

Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 716 of the TERT protein (p.Ala716Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TERT-related conditions (PMID: 18931339, 21931702, 29146883; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39109). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TERT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TERT function (PMID: 18931339, 21931702). This variant disrupts the p.Ala716 amino acid residue in TERT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30203795). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dyskeratosis congenita, autosomal dominant 2 Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant dyskeratosis congenita 2 and autosomal recessive dyskeratosis congenita 4 (MIM#613989) and telomere-related pulmonary fibrosis and/or bone marrow failure 1 (MIM#614742). (I) 0108 - This gene is associated with both recessive and dominant disease. No specific genotype-phenotype correlations have been established (PMID: 20301779). (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability is well reported for dyskeratosis congenita (PMID: 20301779). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Ala716Thr) has been reported as pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in multiple unrelated individuals with cytopenia, aplastic anaemia or bone marrow failure, including heterozygotes without a known 2nd variant in this gene (PMIDs: 18931339, 21931702, 29596117, 33003434, 34565437). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Reduced telomere length has been reported in affected individuals with this variant (PMIDs: 18931339, 21931702). In addition, telomeric repeat amplification protocol (TRAP) assay using transfected cells showed this variant resulted in reduced telomerase activity (PMIDs: 18931339, 21931702). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dyskeratosis congenita Pathogenic:1

May 10, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A716V variant (also known as c.2147C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2147. The alanine at codon 716 is replaced by valine, an amino acid with similar properties. This variant was previously identified in a child with severe pancytopenia and a significant family history of aplastic anemia and lung disease; the p.A716V variant showed a significant reduction in telomerase activity (14% of wild type), and telomere length was determined to be below the 1st percentile of normal controls for this patient (Du HY et al. Blood., 2009 Jan;113(2):309-16). In our internal cohort, this variant was detected in an individual with aplastic anemia, pulmonary fibrosis, and exudative retinopathy. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Aplastic anemia Other:1

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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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.91		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs199422298; hg19: chr5-1278895; COSMIC: COSV57213741;