rs61750414
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000466.3(PEX1):c.2391_2392del(p.Arg798SerfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,638 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PEX1
NM_000466.3 frameshift
NM_000466.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.41
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
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-92501913-CGA-C is Pathogenic according to our data. Variant chr7-92501913-CGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92501913-CGA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX1 | NM_000466.3 | c.2391_2392del | p.Arg798SerfsTer35 | frameshift_variant | 14/24 | ENST00000248633.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX1 | ENST00000248633.9 | c.2391_2392del | p.Arg798SerfsTer35 | frameshift_variant | 14/24 | 1 | NM_000466.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251226Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135786
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461506Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727070
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Zellweger spectrum disorders Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg798Serfs*35) 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 (rs61750414, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 16088892). ClinVar contains an entry for this variant (Variation ID: 188851). For these reasons, this variant has been classified as Pathogenic. - |
Heimler syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 19, 2023 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 16, 2020 | Variant summary: PEX1 c.2391_2392delTC (p.Arg798SerfsX35) 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 8e-06 in 251226 control chromosomes. c.2391_2392delTC has been reported in the literature in at-least one individual affected with Zellweger Syndrome and has been subsequently cited by others (example, Maxwell_2005, Crane_2005, Ebberink_2011). 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 25, 2014 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at