rs267608176
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):c.1842del(p.Glu615LysfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
PEX1
NM_000466.3 frameshift
NM_000466.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.04
Genes affected
PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]
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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 7-92506305-CT-C is Pathogenic according to our data. Variant chr7-92506305-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92506305-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.1842del | p.Glu615LysfsTer30 | frameshift_variant | 11/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.1842del | p.Glu615LysfsTer30 | frameshift_variant | 11/24 | 1 | NM_000466.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251282Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135816
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460032Hom.: 0 Cov.: 28 AF XY: 0.00000413 AC XY: 3AN XY: 726498
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zellweger spectrum disorders Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Glu615Lysfs*30) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs267608176, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of Zellweger spectrum disorder (PMID: 19105186, 21031596). This variant is also known as c.1840delA. ClinVar contains an entry for this variant (Variation ID: 371703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 26, 2020 | - - |
PEX1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 10, 2023 | The PEX1 c.1842delA variant is predicted to result in a frameshift and premature protein termination (p.Glu615Lysfs*30). This variant has been reported in individuals with clinical features of PEX1-related disorders (Reported as c.1840delA in Yik et al 2009. PubMed ID: 19105186; Yépez VA et al 2022. PubMed ID: 35379322). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92135619-CT-C). Frameshift variants in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 09, 2024 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2019 | Variant summary: PEX1 c.1842delA (p.Glu615LysfsX30) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251282 control chromosomes. c.1842delA has been reported in the literature in individuals affected with biochemically confirmed diagnosis of Zellweger Syndrome (Yik_2009, Ebberink_2010). 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 clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 1B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2016 | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2016 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at