PAM
protein-codingpeptidylglycine alpha-amidating monooxygenase
Gene summary
This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~275.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PAM variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001177306.2. 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 | 5 | 5 | 3 | 13 | ||
| missense | 89 | 3 | 3 | 95 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 0 | 0 | 103 | 8 | 6 | 117 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001170777.1 | 25 | MANE Select | |
| Ensembl | ENSP00000396493.3 | 25 | MANE Select | |
| RefSeq | NP_000910.2 | 25 | Standard | |
| RefSeq | NP_001306872.1 | 26 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pam | Danio rerio | Structure: brush border epithelial cell Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- peptide amidation
- response to hypoxia
- long-chain fatty acid metabolic process
- regulation of transcription by RNA polymerase II
- central nervous system development
Molecular Function
- peptidylglycine monooxygenase activity
- peptidylamidoglycolate lyase activity
- copper ion binding
- calcium ion binding
- protein binding
Cellular Component
- extracellular region
- trans-Golgi network
- plasma membrane
- cell surface
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000304400
- Coding exons
- 25
- Length
- 277125
- Individuals with no LoFs
- 125698
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 50
- Defined
- 125748
- p
- 0.000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.960 | 464 | 526 | 0.882 | 0.0000260 | 6387 |
| Missense (PolyPhen) | 260 | 301.72 | 0.86173 | 3776 | ||
| Synonymous | 0.567 | 174 | 184 | 0.947 | 0.00000916 | 1858 |
| Loss of Function | 4.38 | 19 | 53.6 | 0.355 | 0.00000273 | 646 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Bifunctional enzyme that catalyzes 2 sequential steps in C-terminal alpha-amidation of peptides. The monooxygenase part produces an unstable peptidyl(2-hydroxyglycine) intermediate that is dismutated to glyoxylate and the corresponding desglycine peptide amide by the lyase part. C-terminal amidation of peptides such as neuropeptides is essential for full biological activity.;
Recessive Scores
- pRec
- 0.271
Intolerance Scores
- LoFtool
- 0.191
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.856
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |