chr5-1293560-GTCC-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2
The NM_198253.3(TERT):c.1323_1325delGGA(p.Glu441del) variant causes a disruptive 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).
Frequency
Consequence
NM_198253.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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TERT | NM_198253.3 | c.1323_1325delGGA | p.Glu441del | disruptive_inframe_deletion | Exon 2 of 16 | ENST00000310581.10 | NP_937983.2 | |
TERT | NM_001193376.3 | c.1323_1325delGGA | p.Glu441del | disruptive_inframe_deletion | Exon 2 of 15 | NP_001180305.1 | ||
TERT | NR_149162.3 | n.1402_1404delGGA | non_coding_transcript_exon_variant | Exon 2 of 13 | ||||
TERT | NR_149163.3 | n.1402_1404delGGA | non_coding_transcript_exon_variant | Exon 2 of 13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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TERT | ENST00000310581.10 | c.1323_1325delGGA | p.Glu441del | disruptive_inframe_deletion | Exon 2 of 16 | 1 | NM_198253.3 | ENSP00000309572.5 | ||
TERT | ENST00000334602.10 | c.1323_1325delGGA | p.Glu441del | disruptive_inframe_deletion | Exon 2 of 15 | 1 | ENSP00000334346.6 | |||
TERT | ENST00000460137.6 | n.1323_1325delGGA | non_coding_transcript_exon_variant | Exon 2 of 13 | 1 | ENSP00000425003.1 | ||||
TERT | ENST00000656021.1 | n.1323_1325delGGA | non_coding_transcript_exon_variant | Exon 2 of 17 | ENSP00000499759.1 |
Frequencies
GnomAD3 genomes AF: 0.00231 AC: 351AN: 152216Hom.: 2 Cov.: 34
GnomAD3 exomes AF: 0.00164 AC: 246AN: 149562Hom.: 0 AF XY: 0.00165 AC XY: 132AN XY: 80200
GnomAD4 exome AF: 0.00302 AC: 4218AN: 1395092Hom.: 6 AF XY: 0.00290 AC XY: 1992AN XY: 687338
GnomAD4 genome AF: 0.00230 AC: 351AN: 152334Hom.: 2 Cov.: 34 AF XY: 0.00204 AC XY: 152AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
TERT: BP3, BS1 -
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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. -
This variant is associated with the following publications: (PMID: 27153395, 22853774, 21520173, 23901009, 19147845, 19674077, 19760749, 15814878, 28951115) -
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not specified Benign:2
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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
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Dyskeratosis congenita Benign:2
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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. -
Hepatoblastoma Pathogenic:1
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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
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
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Idiopathic Pulmonary Fibrosis;C3151443:Dyskeratosis congenita, autosomal dominant 2 Benign:1
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Dyskeratosis Congenita, Recessive Benign:1
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TERT-related disorder Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at