FOLH1
protein-codingfolate hydrolase 1, the group of M28 metallopeptidases
Gene summary
This gene encodes a type II transmembrane glycoprotein belonging to the M28 peptidase family. The protein acts as a glutamate carboxypeptidase on different alternative substrates, including the nutrient folate and the neuropeptide N-acetyl-l-aspartyl-l-glutamate and is expressed in a number of tissues such as prostate, central and peripheral nervous system and kidney. A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. In the prostate the protein is up-regulated in cancerous cells and is used as an effective diagnostic and prognostic indicator of prostate cancer. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants encoding several different isoforms. [provided by RefSeq, Jul 2010]
- FOLH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~63.5 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 FOLH1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004476.3. 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 | 3 | 1 | 4 | |||
| missense | 65 | 5 | 2 | 72 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 67 | 8 | 3 | 78 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004467.1 | 19 | MANE Select | |
| Ensembl | ENSP00000256999.2 | 19 | MANE Select | |
| RefSeq | NP_001014986.1 | 18 | Standard | |
| RefSeq | NP_001180400.1 | 19 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
- Vitamin digestion and absorption - Homo sapiens (human)
- One Carbon Metabolism
- Metabolism of amino acids and derivatives
- Metabolism
Biological Process
- proteolysis
- folic acid-containing compound metabolic process
- cellular amino acid biosynthetic process
- C-terminal protein deglutamylation
Molecular Function
- metallocarboxypeptidase activity
- peptidase activity
- dipeptidase activity
- metal ion binding
- Ac-Asp-Glu binding
Cellular Component
- cytoplasm
- plasma membrane
- integral component of plasma membrane
- cell surface
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000256999
- Coding exons
- 19
- Length
- 62036
- Individuals with no LoFs
- 125682
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 63
- Defined
- 125745
- p
- 0.000251
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.51 | 295 | 378 | 0.781 | 0.0000182 | 4878 |
| Missense (PolyPhen) | 98 | 155.02 | 0.63218 | 1960 | ||
| Synonymous | 0.184 | 128 | 131 | 0.979 | 0.00000644 | 1398 |
| Loss of Function | 2.84 | 20 | 39.2 | 0.510 | 0.00000197 | 509 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00018 | rare |
| Latino/Admixed American | 0.00066 | 0.00058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00020 | 0.00019 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0.00078 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Has both folate hydrolase and N-acetylated-alpha-linked- acidic dipeptidase (NAALADase) activity. Has a preference for tri- alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N- aceylaspartylglutamate (NAAG), thereby releasing glutamate. Involved in prostate tumor progression.;
Recessive Scores
- pRec
- 0.432
Intolerance Scores
- LoFtool
- 0.898
- RVIS EVS
- 1.33
- RVIS percentile EVS
- 94.21
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.604
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |