rs121918661

chr5-1294282-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS1

The NM_198253.3(TERT):c.604G>A(p.Ala202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,594,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A202A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:16 B:5 O:1
• Conservation: PhyloP100: -1.97

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01952967).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000147 (212/1441744) while in subpopulation MID AF= 0.00594 (34/5720). AF 95% confidence interval is 0.00437. There are 1 homozygotes in gnomad4_exome. There are 125 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.604G>A	p.Ala202Thr	missense_variant	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.604G>A	p.Ala202Thr	missense_variant	2/15
TERT	NR_149162.3	n.683G>A		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.683G>A		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.604G>A	p.Ala202Thr	missense_variant	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.604G>A	p.Ala202Thr	missense_variant	2/15	1		A2
TERT	ENST00000460137.6	c.604G>A	p.Ala202Thr	missense_variant, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.604G>A	p.Ala202Thr	missense_variant, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000316 AC: 66 AN: 208938 Hom.: 1 AF XY: 0.000240 AC XY: 28 AN XY: 116836

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000877

Gnomad ASJ exome AF: 0.000431

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.000147 AC: 212 AN: 1441744 Hom.: 1 Cov.: 35 AF XY: 0.000174 AC XY: 125 AN XY: 717266

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000910

Gnomad4 ASJ exome AF: 0.000270

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000586

Gnomad4 OTH exome AF: 0.000718

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152368 Hom.: 0 Cov.: 34 AF XY: 0.000242 AC XY: 18 AN XY: 74502

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000671 Hom.: 1

Bravo AF: 0.000355

ESP6500AA AF: 0.000476 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000229 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:16 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15885610, 23538340, 23716176, 15814878, 30791107, 30426156, 29416752, 30523342, 20858879, 32089214, 22424236, 23901009) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -

not specified Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2017	The p.Ala202Thr (NM_198253.2 c.604G>A) variant in TERT has been reported in hete rozygosity in 2 individuals with clinical features of Dyskeratosis congenita an d related disorders (Yamaguchi 2005; ClinVar Variation ID#12729). It was also id entified in another family and did not segregate with disease ( Vulliamy 2005). This variant has been identified in 0.205% (13/6,346) of Latino chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 21918661). In vitro functional studies reportedly suggest that the p.Ala202Thr v ariant may impact protein function (Zaug 2013 and Yamaguchi 2005); however, thes e types of assays may not accurately represent biological function. The amino ac id position is not conserved in mammals and most computational predictions progr ams do not suggest an impact. In summary, the clinical significance of the p.Ala 202Thr variant is uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2019	- -

Dyskeratosis congenita, autosomal dominant 2 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 23, 2022	The TERT c.604G>A (p.Ala202Thr) missense change has a maximum subpopulation frequency of 0.085% in gnomAD v2.1.1 including one homozygote (https://gnomad.broadinstitute.org/). This variant has been reported as heterozygous in individuals with a personal and/or family history of aplastic anemia and myelodysplastic syndrome (PMID: 15814878, 30523342) and was found to segregate with short telomeres in one family (PMID: 15814878). This variant has also been reported as homozygous in an individual with oligodontia, abnormality of the fingernails, hidrotic ectodermal dysplasia, sparse hair, dystrophic fingernails (PMID: 27848944). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have shown telomerase activity at reduced to approximately 50-80% of WT (PMID: 15814878, 23901009). In summary, the evidence currently available is insufficient to determine the role of this variant in dyskeratosis congenita. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 25, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 26, 2019	- -

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 07, 2005	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 25, 2018	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. -

Aplastic anemia Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 25, 2018	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary cancer-predisposing syndrome;C0265965:Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2018

The p.A202T variant (also known as c.604G>A), located in coding exon 2 of the TERT gene, results from a G to A substitution at nucleotide position 604. The alanine at codon 202 is replaced by threonine, an amino acid with similar properties. This variant was identified in individuals with aplastic anemia (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24; Scheinberg P et al. JAMA, 2010 Sep;304:1358-64) as well as in healthy individuals (Calado RT et al. Blood, 2009 Sep;114:2236-43; Chen R et al. Cell, 2012 Mar;148:1293-307). In addition, telomerase activity studies have had conflicting results, with <1% activity in one assay and 88% in another compared to wild type (Yamaguchi H et al. N. Engl. J. Med., 2005 Apr;352:1413-24; Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Dyskeratosis congenita Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 31, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

TERT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	2.4
Dann	Benign	0.97
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.020	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.23	N;N
REVEL	Uncertain	0.55
Sift	Benign	0.56	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.18	B;B
Vest4		0.50
MVP		0.98
MPC		1.0
ClinPred		0.0071	T
GERP RS		0.90
Varity_R		0.047
gMVP		0.71

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

Other links and lift over

dbSNP: rs121918661; hg19: chr5-1294397;