PEX19
protein-codingperoxisomal biogenesis factor 19, the group of Peroxins
Gene summary
This gene is necessary for early peroxisomal biogenesis. It acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. These disorders have at least 14 complementation groups, with more than one phenotype being observed for some 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 are a cause of Zellweger syndrome (ZWS), as well as peroxisome biogenesis disorder complementation group 14 (PBD-CG14), which is also known as PBD-CGJ. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]
- PXF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: ClinGen
The relationship between PEX19 and peroxisome biogenesis disorder (type 12A (Zellweger) included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX19 encodes a peroxisome membrane protein involved in early peroxisome membrane biosynthesis prior to matrix protein import. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX19 belongs to complementation group J and mutations in the gene result in cells devoid of peroxisomal remnants (Waterham and Ebberink 2012, PMID 22871920) or with a small number of enlarged peroxisomes (Ebberink et al, 2010, PMID 20647552). PEX19 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1999. (Matsuzono et al, PMID: 10051604). At least 3 nonsense or frameshift variants have been reported in humans. 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 5 probands in 5 publications (PMID: 10051604, 20683989, 21031596, 30561787, 36931687). Variants in this gene segregated with 4 additional family members. The mechanism for disease is expected to be homozygous loss of function. Summary of experimental data (4 points): This gene-disease association is supported by in vitro functional assays (PMIDs 21669930, 28526747, 12096124, 10051604). PEX19 interacts with PEX3, PEX11B and PEX16. In summary, the PEX19-peroxisome biogenesis disorder gene-disease relationship is definitive. 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 January 17, 2020 (SOP Version 7). This gene-disease pair was originally evaluated by the Peroxisomal Disorders on January 17, 2020. It was reevaluated on April 27, 2023. As a result of this reevaluation, the classification did not change. The genetic evidence was updated and scored according SOP v9 and a new case report added, which maxed out the genetic evidence score.
Inheritance Pattern: AR
Disease ID:MONDO:0019609
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013951
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013951
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013951
Submitter: G2P
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 PEX19 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002857.4. 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 | 2 | 99 | 101 | |||
| missense | 1 | 173 | 5 | 179 | ||
| nonsense | 4 | 2 | 6 | |||
| start loss | 0 | |||||
| frameshift | 6 | 6 | 1 | 13 | ||
| splice donor/acceptor (+/-2bp) | 9 | 3 | 12 | |||
| Total | 10 | 18 | 179 | 104 | 0 | 311 |
Highest pathogenic variant AF is 0.000023549243
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002848.1 | 8 | MANE Select | |
| Ensembl | ENSP00000357051.5 | 8 | MANE Select | |
| RefSeq | NP_001180573.1 | 8 | Standard | |
| Ensembl | ENSP00000376054.2 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Peroxisome - Homo sapiens (human)
- ABC transporters in lipid homeostasis
- Transport of small molecules
- ABC-family proteins mediated transport
Biological Process
- protein targeting to peroxisome
- peroxisome organization
- peroxisome fission
- protein import into peroxisome membrane
- protein stabilization
Molecular Function
- protein binding
- peroxisome membrane class-1 targeting sequence binding
- protein N-terminus binding
- ATPase binding
Cellular Component
- nucleoplasm
- cytoplasm
- peroxisome
- peroxisomal membrane
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368072
- Coding exons
- 8
- Length
- 9537
- Individuals with no LoFs
- 125721
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 27
- Defined
- 125748
- p
- 0.000107
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.776 | 190 | 162 | 1.17 | 0.00000837 | 1984 |
| Missense (PolyPhen) | 51 | 51.81 | 0.98437 | 691 | ||
| Synonymous | -0.668 | 70 | 63.2 | 1.11 | 0.00000377 | 555 |
| Loss of Function | 1.75 | 8 | 15.4 | 0.518 | 6.70e-7 | 194 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00012 | 0.00012 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53. {ECO:0000269|PubMed:10051604, ECO:0000269|PubMed:10704444, ECO:0000269|PubMed:11259404, ECO:0000269|PubMed:11883941, ECO:0000269|PubMed:14709540, ECO:0000269|PubMed:15007061}.;
- Disease
- DISEASE: Peroxisome biogenesis disorder 12A (PBD12A) [MIM:614886]: 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:10051604}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.255
Intolerance Scores
- LoFtool
- 0.343
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.99
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |