5-1254479-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_198253.3(TERT):c.3184G>A(p.Ala1062Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,612,636 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. A1062S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.020 (339 hom.)
• Consequence: TERT NM_198253.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:2
• Conservation: PhyloP100: -3.62

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_198253.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.053545833).
• BP6: Variant 5-1254479-C-T is Benign according to our data. Variant chr5-1254479-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, not_provided=1, Benign=5}. Variant chr5-1254479-C-T is described in Lovd as [Benign]. Variant chr5-1254479-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0133 (2031/152222) while in subpopulation NFE AF= 0.023 (1566/67986). AF 95% confidence interval is 0.0221. There are 24 homozygotes in gnomad4. There are 903 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.3184G>A	p.Ala1062Thr	missense_variant	15/16	ENST00000310581.10
TERT	NM_001193376.3	c.2995G>A	p.Ala999Thr	missense_variant	14/15
TERT	NR_149162.3	n.2892G>A		non_coding_transcript_exon_variant	12/13
TERT	NR_149163.3	n.2856G>A		non_coding_transcript_exon_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.3184G>A	p.Ala1062Thr	missense_variant	15/16	1	NM_198253.3	P2
	ENST00000666708.1	n.289-195C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2032 AN: 152102 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0124 AC: 3056 AN: 246886 Hom.: 41 AF XY: 0.0123 AC XY: 1661 AN XY: 134680

Gnomad AFR exome AF: 0.00256

Gnomad AMR exome AF: 0.00392

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0217

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0201 AC: 29410 AN: 1460414 Hom.: 339 Cov.: 32 AF XY: 0.0195 AC XY: 14178 AN XY: 726536

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0133 AC: 2031 AN: 152222 Hom.: 24 Cov.: 33 AF XY: 0.0121 AC XY: 903 AN XY: 74434

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0183 Hom.: 13

Bravo AF: 0.0126

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00336 AC: 14

ESP6500EA AF: 0.0220 AC: 186

ExAC AF: 0.0125 AC: 1507

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0199

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2020	Variant classified as Uncertain Risk Allele. TERT c.3184G>A (p.Ala1062Thr) has been associated with increased risk for acute myeloid leukemia. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of non-Finnish European ancestry (2.1%, Genome Aggregation Database (gnomAD); rs35719940) and is present in ClinVar (ID: 39121). Several small studies implicate this variant is associated with a number of different hematological and pulmonary conditions including pulmonary fibrosis (Tsakiri 2007, Alder 2008), AML (Calado 2009, Aref 2014), DL-BCL and CLL (Hills 2009) and cirrhosis (Calado 2011). Functional studies from all but one group (Calado 2011) suggest that that this variant does not have a significant impact on telomerase activity (Alder 2008, Gramatges 2013, Zaug 2013, Zhang 2014, Hoffman 2017). In summary, it is uncertain if this variant is a risk factor for TERT-related conditions. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TERT: PP2, BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 09, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	This variant is associated with the following publications: (PMID: 17460043, 22476886, 23538340, 23901009, 19147845, 18753630, 21520173, 25108601, 23716176, 27153395, 28813500, 28154186, 22093366, 15814878, 19796246, 24983628) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2023	- -

Aplastic anemia Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2016

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Dyskeratosis congenita, autosomal dominant 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Breast carcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Leukemia, acute myeloid, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 27, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.033
Dann	Benign	0.89
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.054	T;T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	2.0e-13	A;A;A
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.64	N;N
REVEL	Benign	0.21
Sift	Benign	0.75	T;T
Sift4G	Benign	0.22	T;D
Polyphen		0.34	B;B
Vest4		0.020
MPC		1.0
ClinPred		0.00055	T
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.041

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: rs35719940; hg19: chr5-1254594; COSMIC: COSV57200744;