PEX14
protein-codingperoxisomal biogenesis factor 14, the group of Peroxins
Gene summary
This gene encodes an essential component of the peroxisomal import machinery. The protein is integrated into peroxisome membranes with its C-terminus exposed to the cytosol, and interacts with the cytosolic receptor for proteins containing a PTS1 peroxisomal targeting signal. The protein also functions as a transcriptional corepressor and interacts with a histone deacetylase. A mutation in this gene results in one form of Zellweger syndrome. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~158.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019609
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013952
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013952
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: ClinGen
The relationship between PEX14 and peroxisome biogenesis disorder, an autosomal recesiive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. PEX14 encodes a membrane-bound peroxisomal protein that interacts with PEX13 to form the peroxisomal docking site for the PTS1 receptor PEX5 (reviewed in Waterham and Ebberink, 2016; PMID: 22871920). Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis. There are at least 14 PEX genes implicated in peroxisome biogenesis disorders, with PEX14 being one of the least commonly affected genes in patients (Steinberg et al., 2003; PMID: 20301621). Variants in PEX14 were first reported in humans with peroxisomal biogenesis disorder in 2004 (Shimozawa et al., PMID: 15146459). There are four patients reported in the literature with four unique variants (nonsense, deletion, and missense) (Shimozawa et al., 2004; PMID: 15146459; Huybrechts et al., 2009; PMID: 21686775; Komatsuzaki et al., 2015; PMID: 26627464; Galvez-Ruiz et al., 2018; PMID: 30224891). The relationship between PEX14 and peroxisome biogenesis disorder is supported by experimental evidence including a biochemical function similar to other PEX genes implicated in peroxisome biogenesis disorders (Waterham et al., 2012, PMID 22871920), in vitro assays (Albertini et al., 1997; PMID: 9094717; Shimozawa et al., 2004; PMID: 15146459) and a protein interaction with PEX5 and PEX13 (Albertini et al., 1997; PMID: 9094717), which have also been implicated in the disorder. In summary, PEX14 is definitively associated with peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on September 20, 2019.
Inheritance Pattern: AR
Disease ID:MONDO:0013952
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013952
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PEX14 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004565.3. 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 | 7 | 140 | 1 | 148 | ||
| missense | 185 | 15 | 1 | 201 | ||
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 3 | 8 | ||
| Total | 3 | 4 | 199 | 155 | 2 | 363 |
Highest pathogenic variant AF is 0.0000037173616
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004556.1 | 9 | MANE Select | |
| Ensembl | ENSP00000349016.4 | 9 | MANE Select | |
| Ensembl | ENSP00000465473.1 | 6 | Standard | |
| Ensembl | ENSP00000559338.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Peroxisome - Homo sapiens (human)
- Beta Oxidation of Very Long Chain Fatty Acids
- Oxidation of Branched Chain Fatty Acids
- Adrenoleukodystrophy, X-linked
- Carnitine-acylcarnitine translocase deficiency
Biological Process
- protein targeting to peroxisome
- peroxisome organization
- protein import into peroxisome matrix
- protein import into peroxisome matrix, docking
- protein import into peroxisome matrix, translocation
Molecular Function
- transcription corepressor activity
- signaling receptor binding
- protein binding
- microtubule binding
- protein N-terminus binding
Cellular Component
- fibrillar center
- nucleus
- peroxisome
- peroxisomal membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356607
- Coding exons
- 9
- Length
- 158471
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125748
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.27 | 168 | 221 | 0.759 | 0.0000147 | 2429 |
| Missense (PolyPhen) | 44 | 69.639 | 0.63183 | 755 | ||
| Synonymous | -0.908 | 112 | 100 | 1.12 | 0.00000807 | 742 |
| Loss of Function | 3.15 | 5 | 20.3 | 0.246 | 0.00000102 | 214 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000036 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Peroxisome membrane protein that is an essential component of the peroxisomal import machinery. Functions as a docking factor for the predominantly cytoplasmic PTS1 receptor (PEX5). Plays a key role for peroxisome movement through a direct interaction with tubulin. {ECO:0000269|PubMed:21525035, ECO:0000269|PubMed:9653144}.;
- Disease
- DISEASE: Peroxisome biogenesis disorder complementation group K (PBD-CGK) [MIM:614887]: A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS). {ECO:0000269|PubMed:15146459}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 13A (PBD13A) [MIM:614887]: A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life. {ECO:0000269|PubMed:15146459}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.217
Intolerance Scores
- LoFtool
- 0.372
- RVIS EVS
- -0.49
- RVIS percentile EVS
- 22.65
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.933
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |