chr19-43526608-ACT-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014297.5(ETHE1):c.131_132delAG(p.Glu44fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
ETHE1
NM_014297.5 frameshift
NM_014297.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.42
Genes affected
ETHE1 (HGNC:23287): (ETHE1 persulfide dioxygenase) This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]
ZNF575 (HGNC:27606): (zinc finger protein 575) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-43526608-ACT-A is Pathogenic according to our data. Variant chr19-43526608-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 504493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-43526608-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ETHE1 | NM_014297.5 | c.131_132delAG | p.Glu44fs | frameshift_variant | 2/7 | ENST00000292147.7 | NP_055112.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151686Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251040Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135782
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461842Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 727222
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GnomAD4 genome 0.00000659 AC: 1AN: 151686Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74052
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ethylmalonic encephalopathy Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Glu44Valfs*62) in the ETHE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETHE1 are known to be pathogenic (PMID: 14732903, 19136963). This variant is present in population databases (rs761827730, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with ethylmalonic encephalopathy (PMID: 14732903). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as E44fsX105. ClinVar contains an entry for this variant (Variation ID: 504493). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 24, 2018 | Variant summary: ETHE1 c.131_132delAG (p.Glu44ValfsX62) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 246334 control chromosomes (gnomAD and publication). The variant, c.131_132delAG, has been reported in the literature in individuals affected with Ethylmalonic Encephalopathy, in compound heterozygotes and one homozygote (Boyer_2018, Dionisi-Vici_2016), and was shown to segregate in one family (Tiranti_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One reputable database has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 ethylmalonic encephalopathy (MIM#602473). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to result in NMD have been reported as pathogenic in individuals with ethylmalonic encephalopathy (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as homozygous and compound heterozygous in individuals with ethylmalonic encephalopathy (ClinVar, PMID: 14732903, PMID: 26917598). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 22, 2023 | The observed frameshift c.131_132del(p.Glu44ValfsTer62) variant in ETHE1 gene has been reported previously in homozygous state in individual(s) affected with Ethylmalonic encephalopathy (EE) (Platt et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamic Acid 44, changes this amino acid to Valine residue, and creates a premature Stop codon at position 62 of the new reading frame, denoted p.Glu44ValfsTer62. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Tiranti et al., 2009). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 27, 2024 | - - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at