PEX7
protein-codingperoxisomal biogenesis factor 7, the group of WD repeat domain containing|Peroxins
Gene summary
This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100272
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0013945
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013945
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008972
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008972
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0008972
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013945
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008972
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: ClinGen
The relationship between PEX7 and peroxisome biogenesis disorder (type 9B and type 1 Rhizomelic chondrodysplasia punctata included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX7 encodes a receptor for some of the peroxisomal matrix proteins and is involved in the PTS2 import pathway. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX7 belongs to complementation group 11, and mutations in the gene result in peroxisomes devoid of PTS2 import (Braverman et al, 2012, Gene Reviews). PEX7 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1997. (Braverman et al, PMID: 9090381; Motley et al, PMID: 9090382; Purdue et al, PMID: 9090383). At least 38 nonsense, splice site, frameshift, deletion/duplication and missense variants have been reported in humans in the ClinVar database. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 8 probands in 6 publications (PMID: 9090381, 12325024, 26587300, 28742517, 10083738, 25800479). More evidence is available in the literature, but the maximum score (12 points) for genetic evidence is reached. The recurring founder variant, Leu292Ter is most frequently reported and accounts for 51% of disease alleles. The mechanism for disease is expected to be biallelic loss of function. Summary of experimental data (5 points): This gene-disease association is supported by in vitro functional assays and animal models. PEX7 interacts with PEX5, which is involved in the PTS1 import pathway but also acts as a coreceptor for the PEX7-cargo protein complex in the PTS2 pathway (PMID: 26450166, 25538232). Mouse models of PEX7 recapitulate the human disease (PMIDs: 12915479, 20060764) and wild-type PEX7 restores peroxisome import in patient-derived PEX7-deficient cells (PMIDs: 9090381). In summary, PEX7 is definitively associated with autosomal recessive Peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on February 14, 2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0009958
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Biochemical
Rationale: Dietary measures (eg, phytanic acid restriction, high calorie diet) can help with dermatologic and neurologic manifestations; Surveillance and medical carefor cardiac arrhythmias and cardiomyopathy can reduce morbidity/mortality; Plasmapheresis/lipid apheresis may be used; Fasting and ibuprofen should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PEX7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000288.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 174 | 184 | |||
| missense | 1 | 14 | 181 | 6 | 202 | |
| nonsense | 11 | 24 | 2 | 37 | ||
| start loss | 0 | |||||
| frameshift | 38 | 42 | 4 | 84 | ||
| splice donor/acceptor (+/-2bp) | 7 | 27 | 4 | 38 | ||
| Total | 57 | 107 | 201 | 180 | 0 | 545 |
Highest pathogenic variant AF is 0.0006833928
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000279.1 | 10 | MANE Select | |
| Ensembl | ENSP00000315680.3 | 10 | MANE Select | |
| RefSeq | NP_001397874.1 | 10 | Standard | |
| Ensembl | ENSP00000356730.4 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Peroxisome - Homo sapiens (human)
- Metabolism of proteins
- Peroxisomal protein import
Biological Process
- neuron migration
- endochondral ossification
- protein targeting to peroxisome
- fatty acid beta-oxidation
- peroxisome organization
Molecular Function
- peroxisome matrix targeting signal-2 binding
- protein binding
- enzyme binding
- protein homodimerization activity
Cellular Component
- peroxisome
- peroxisomal membrane
- peroxisomal matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318471
- Coding exons
- 10
- Length
- 91359
- Individuals with no LoFs
- 125601
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 147
- Defined
- 125748
- p
- 0.000585
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.497 | 145 | 163 | 0.890 | 0.00000774 | 2096 |
| Missense (PolyPhen) | 50 | 50.659 | 0.98699 | 674 | ||
| Synonymous | -0.747 | 71 | 63.4 | 1.12 | 0.00000351 | 621 |
| Loss of Function | 0.142 | 19 | 19.7 | 0.966 | 9.40e-7 | 226 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00093 | 0.00093 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to the N-terminal PTS2-type peroxisomal targeting signal and plays an essential role in peroxisomal protein import.;
- Disease
- DISEASE: Rhizomelic chondrodysplasia punctata 1 (RCDP1) [MIM:215100]: A peroxisome biogenesis disorder. It is characterized by severely disturbed endochondral bone formation, rhizomelic shortening of femur and humerus, vertebral disorders, dwarfism, cataract, cutaneous lesions, facial dysmorphism, and severe mental retardation with spasticity. {ECO:0000269|PubMed:9090381}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 9B (PBD9B) [MIM:614879]: A peroxisome biogenesis disorder with unusually mild clinical and biochemical manifestations. Affected individuals manifest a variable phenotype similar to, and in some cases indistinguishable from, classic Refsum disease. Variable features include ocular abnormalities, sensorimotor neuropathy, ichthyosis, deafness, chondrodysplasia punctata without rhizomelia or growth failure. {ECO:0000269|PubMed:12522768}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.200
Intolerance Scores
- LoFtool
- 0.616
- RVIS EVS
- 0.01
- RVIS percentile EVS
- 54.95
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.584
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |