XPNPEP3
protein-codingX-prolyl aminopeptidase 3, the group of M24 metallopeptidase family|Aminopeptidases
Gene summary
The protein encoded by this gene belongs to the family of X-pro-aminopeptidases that utilize a metal cofactor, and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of renal cells, and have a role in ciliary function. Mutations in this gene are associated with nephronophthisis-like nephropathy-1. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene, however, expression of some of these isoforms in vivo is not known.[provided by RefSeq, Mar 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~75.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019742
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013163
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013163
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013163
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013163
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013163
Submitter: ClinGen
The *XPNPEP3* gene is located on chromosome at 22q13.2 and encodes a member of the family of X-pro-aminopeptidases that utilize a metal cofactor and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of kidney cells and have a role in ciliary function. (provided by RefSeq, Mar 2011). *XPNPEP3* was first reported in relation to autosomal recessive Nephronophthisis-like Nephropathy 1 (NPHPL1) in 2010 (O'Toole et al. PMID: 20179356). The mechanism of disease is biallelic loss of function. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Variants in this gene have been reported in at least 6 probands in 5 publications (PMID: 29383790, 32660933,37599822,38035175, DOI: 10.1681/ASN.20233411S1571a). Unpublished data was included in this curation, a patient with a consistent phenotype associated with compound heterozygous null variants (Molecular Biology Laboratory, Fundació Puigvert and submitted to ClinVar), increasing the final score by 3.0 points for a total of 11.3 genetic evidence points. This gene-disease association is supported by protein interaction, in vitro functional assays, and a zebrafish and a mouse model (PMID: 20179356, 37599822). There is significant correlation between β-catenin nuclear localization and XPNPEP3 levels, suggesting *XPNPEP3* has a role in Wnt-mediated regulation of ciliary development (Kumar et al. 2018; PMID: 29383790, non-scorable evidence). In summary, there is Definitive evidence to support *XPNPEP3* as a cause of an autosomal recessive ciliopathy. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 04/28/2021 (SOP Version 8). It was reevaluated on 6/10/2024 (SOP Version 10). As a result of this reevaluation, the classification changed from Moderate to Definitive.
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; 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
Comments: Avoidance of nephrotoxic medications may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to XPNPEP3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022098.4. 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 | 34 | 36 | |||
| missense | 1 | 129 | 8 | 138 | ||
| nonsense | 3 | 6 | 2 | 11 | ||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 5 | 1 | 8 | ||
| splice donor/acceptor (+/-2bp) | 5 | 3 | 8 | |||
| Total | 6 | 16 | 138 | 42 | 0 | 202 |
Highest pathogenic variant AF is 0.000061959865
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071381.1 | 10 | MANE Select | |
| Ensembl | ENSP00000349658.4 | 10 | MANE Select | |
| RefSeq | NP_001191756.1 | 2 | Standard | |
| Ensembl | ENSP00000394283.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| xpnpep3 | Danio rerio | Structure: head Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- glomerular filtration
- proteolysis
- protein processing
Molecular Function
- aminopeptidase activity
- protein binding
- manganese ion binding
- protein homodimerization activity
- metalloaminopeptidase activity
Cellular Component
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000357137
- Coding exons
- 10
- Length
- 110758
- Individuals with no LoFs
- 125668
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 80
- Defined
- 125748
- p
- 0.000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0995 | 290 | 285 | 1.02 | 0.0000161 | 3316 |
| Missense (PolyPhen) | 81 | 92.522 | 0.87547 | 1025 | ||
| Synonymous | 0.237 | 99 | 102 | 0.970 | 0.00000539 | 1002 |
| Loss of Function | 2.07 | 17 | 29.0 | 0.586 | 0.00000193 | 289 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00065 | 0.00065 | rare |
| Finnish | 0.00037 | 0.00037 | rare |
| European (Non-Finnish) | 0.00035 | 0.00035 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala (PubMed:25609706, PubMed:28476889). Also shows low activity towards peptides with Ala or Ser at the P1 position (PubMed:28476889). {ECO:0000269|PubMed:25609706, ECO:0000269|PubMed:28476889}.;
Recessive Scores
- pRec
- 0.138
Intolerance Scores
- LoFtool
- 0.647
- RVIS EVS
- -0.27
- RVIS percentile EVS
- 34.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.826
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |