chr5-1293560-GTCC-G

Position:

• chr5-1293560-GTCC-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_198253.3(TERT):​c.1323_1325del​(p.Glu441del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,547,426 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E441E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: TERT NM_198253.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:13
• Conservation: PhyloP100: 1.39

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 Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198253.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 5-1293560-GTCC-G is Benign according to our data. Variant chr5-1293560-GTCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212398.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=11, Uncertain_significance=3}. Variant chr5-1293560-GTCC-G is described in Lovd as [Benign]. Variant chr5-1293560-GTCC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0023 (351/152334) while in subpopulation NFE AF= 0.00394 (268/68016). AF 95% confidence interval is 0.00355. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TERT	NM_198253.3	c.1323_1325del	p.Glu441del	inframe_deletion	2/16	ENST00000310581.10
TERT	NM_001193376.3	c.1323_1325del	p.Glu441del	inframe_deletion	2/15
TERT	NR_149162.3	n.1402_1404del		non_coding_transcript_exon_variant	2/13
TERT	NR_149163.3	n.1402_1404del		non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TERT	ENST00000310581.10	c.1323_1325del	p.Glu441del	inframe_deletion	2/16	1	NM_198253.3	P2
TERT	ENST00000334602.10	c.1323_1325del	p.Glu441del	inframe_deletion	2/15	1		A2
TERT	ENST00000460137.6	c.1323_1325del	p.Glu441del	inframe_deletion, NMD_transcript_variant	2/13	1
TERT	ENST00000656021.1	c.1323_1325del	p.Glu441del	inframe_deletion, NMD_transcript_variant	2/17

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152216 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00164 AC: 246 AN: 149562 Hom.: 0 AF XY: 0.00165 AC XY: 132 AN XY: 80200

Gnomad AFR exome AF: 0.000141

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.000528

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00302 AC: 4218 AN: 1395092 Hom.: 6 AF XY: 0.00290 AC XY: 1992 AN XY: 687338

Gnomad4 AFR exome AF: 0.000571

Gnomad4 AMR exome AF: 0.000421

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000504

Gnomad4 FIN exome AF: 0.000502

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152334 Hom.: 2 Cov.: 34 AF XY: 0.00204 AC XY: 152 AN XY: 74488

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00216

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	This variant is associated with the following publications: (PMID: 27153395, 22853774, 21520173, 23901009, 19147845, 19674077, 19760749, 15814878, 28951115) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TERT: BP3, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TERT p.Glu441del variant was identified in the literature in two patients with aplastic anemia, a patient with acute myeloid leukemia and another patient with cirrhosis caused by alcohol (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19674077; Calado_2009_PMID:19147845; Calado_2011_PMID:21520173). The variant was identified in dbSNP (ID: rs377639087), Cosmic, LOVD 3.0 and ClinVar (classified as likely benign by GeneDx, Invitae, Laboratory for Molecular Medicine, Illumina and Genetic Services Laboratory, University of Chicago and as uncertain significance by EGL Genetics and Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago). The variant was identified in control databases in 311 of 180940 chromosomes at a frequency of 0.001719 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 261 of 72072 chromosomes (freq: 0.003621), Other in 14 of 5334 chromosomes (freq: 0.002625), Ashkenazi Jewish in 9 of 8490 chromosomes (freq: 0.00106), European (Finnish) in 10 of 18616 chromosomes (freq: 0.000537), Latino in 11 of 25422 chromosomes (freq: 0.000433), African in 5 of 15812 chromosomes (freq: 0.000316) and South Asian in 1 of 22778 chromosomes (freq: 0.000044), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codon 441; the impact of this alteration on TERT protein function is not known. Functional studies have shown no association with telomere shortening but a decrease in telomere activity has been reported (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19147845). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 22, 2018	p.Glu441del in exon 2 of TERT: This variant is classified as likely benign becau se it has been identified in 0.4% (248/68934) of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs3776 39087). Of note, gibbons have a deletion at this position despite high nearby am ino acid conservation. In addition, although this variant has been reported in s everal studies in individuals with TERT-related conditions, many of these studie s consider the variant to be a polymorphism and the functional evidence availabl e suggests this variant does not have a significant impact on telomere length (Y amaguchi 2005, Calado 2009, Calado 2011, Kirwan 2009, Calado 2011, Fernandez 201 2, Zaug 2013, Maxwell 2016). ACMG/AMP Criteria applied: BS1; BS3_Supporting. -

Interstitial lung disease 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Dyskeratosis congenita Benign:2

Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 10, 2020	The p.Glu441del frameshift variant has a frequency of 0.001719 (311 of 180,940 alleles) in gnomAD v2.1.1 with a maximal allele frequency of 0.003621 (261 of 72,072) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). Pathogenic variants in the TERT gene predispose individuals to dyskeratosis congenita (DKC). While the exact prevalence of DKC is unknown, it is estimated to occur in approximately 1 in 1 million people. Therefore, the population frequency is not consistent with disease (BS1). This variant has been reported as heterozygous in an individual with aplastic anemia (PMID: 19674077) and as homozygous in an individual with acute myeloid leukemia (PMID: 19147845). The variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acid residues (BP3). Results of telomerase activity assays have been conflicting. In several reports, the E441del variant has similar activity to the wild-type allele (PMID: 15814878, 23901009), however another report demonstrated approximately 40% of functional activity as compared to the wild-type allele (PMID: 19147845). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP3. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -

Hepatoblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

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- -

Acute myeloid leukemia;C3151443:Dyskeratosis congenita, autosomal dominant 2;C3553617:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1;C3554574:Melanoma, cutaneous malignant, susceptibility to, 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TERT NM_198253.2 exon 2 p.Glu441del (c.1323_1325del): This variant has been reported in the literature as heterozygous in at 2 least individuals with varying phenotypes (hepatic cirrhosis, aplastic anemia) as well as homozygous in 1 individual with acute myelogenous leukemia (AML) (Yamaguchi 2005 PMID:15814878, Calado 2009 PMID:19674077, Calado 2009 PMID:19147845, Calado 2011 PMIDL21520173). The interpretation of this variant in the current literature is unclear, with at least 2 publications calling this variant a polymorphism (Yamaguchi 2005 PMID:15814878, Maxwell 2016 PMID:27153395). Functional studies are also conflicting, suggesting either a 40% reduction (compared to WT) to near normal effect of this variant on telomerase enzyme activity (Calado 2009 PMID:19147845, Zaug 2013 PMID:23901009). This variant is also present in 0.3% (248/68934) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-1293675-GTCC-G). This variant is present in ClinVar, with discrepant classifications ranging from likely benign to variant of uncertain significance (Variation ID:212398).This variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acids. This is not predicted to alter the reading frame, but the ultimate effect of this variant on the protein is unclear. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Aplastic anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Dyskeratosis Congenita, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

TERT-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

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

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: rs377639087; hg19: chr5-1293675;