chr22-18083639-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001127649.3(PEX26):c.574C>T(p.Arg192Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001127649.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX26 | NM_001127649.3 | c.574C>T | p.Arg192Ter | stop_gained | 3/5 | ENST00000399744.8 | |
PEX26 | NM_017929.6 | c.574C>T | p.Arg192Ter | stop_gained | 4/6 | ||
PEX26 | NM_001199319.2 | c.574C>T | p.Arg192Ter | stop_gained | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX26 | ENST00000399744.8 | c.574C>T | p.Arg192Ter | stop_gained | 3/5 | 1 | NM_001127649.3 | P1 | |
PEX26 | ENST00000329627.11 | c.574C>T | p.Arg192Ter | stop_gained | 4/6 | 1 | P1 | ||
PEX26 | ENST00000428061.2 | c.574C>T | p.Arg192Ter | stop_gained | 3/4 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152074Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251294Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135838
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727188
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152074Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74284
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2019 | Variant summary: PEX26 c.574C>T (p.Arg192X) 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 2e-05 in 251294 control chromosomes (gnomAD). c.574C>T has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink_2010, Steinberg_2004). These data indicate that the variant may be associated with disease. A publication, Guder_2019, performed a functional study to assess the pathophysiological relevance of PEX26 oligomerization and found the variant of interest to not oligomerize but was still able to interact with PEX6. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 17, 2023 | The PEX26 c.574C>T (p.Arg192Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported with a second pathogenic PEX26 variant in an individual with clinical and laboratory features consistent with peroxisome biogenesis disorder (PMID: 15542397). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database and has been classified as pathogenic by at least three submitters in ClinVar. The c.574C>T variant was detected in a homozygous state. Based on the available evidence, the c.574C>T (p.Arg192Ter) variant is classified as pathogenic for peroxisome biogenesis disorder. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34804114, 25525159, 34426522, 12851857, 15542397, 19105186, 21031596) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 26, 2023 | - - |
Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Arg192*) in the PEX26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with peroxisome biogenesis disorders-Zellweger syndrome spectrum (PMID: 15542397). ClinVar contains an entry for this variant (Variation ID: 928563). For these reasons, this variant has been classified as Pathogenic. - |
Peroxisome biogenesis disorder 7A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at