MANF
protein-codingmesencephalic astrocyte derived neurotrophic factor
Gene summary
The protein encoded by this gene is localized in the endoplasmic reticulum (ER) and golgi, and is also secreted. Reducing expression of this gene increases susceptibility to ER stress-induced death and results in cell proliferation. Activity of this protein is important in promoting the survival of dopaminergic neurons. The presence of polymorphisms in the N-terminal arginine-rich region, including a specific mutation that changes an ATG start codon to AGG, have been reported in a variety of solid tumors; however, these polymorphisms were later shown to exist in normal tissues and are thus no longer thought to be tumor-related. [provided by RefSeq, Apr 2014]
- ARMET
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0957997
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Neurologic
Intervention: Audiologic/Otolaryngologic; Endocrine
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve early-onset diabetes mellitus, and awareness may allow early identification and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MANF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006010.6. 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 | 1 | 1 | 2 | |||
| missense | 28 | 28 | ||||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 1 | 2 | 31 | 1 | 1 | 36 |
Highest pathogenic variant AF is 9.2076453e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006001.5 | 4 | MANE Select | |
| Ensembl | ENSP00000432799.3 | 4 | MANE Select | |
| Ensembl | ENSP00000405280.1 | 3 | Standard | |
| Ensembl | ENSP00000658791.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| manf | Danio rerio | Structure: ventral thalamus Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet degranulation
- Response to elevated platelet cytosolic Ca2+
- Platelet activation, signaling and aggregation
- Hemostasis
Biological Process
- platelet degranulation
- response to unfolded protein
- regulation of signaling receptor activity
- neuron projection development
- dopaminergic neuron differentiation
Molecular Function
- RNA binding
- growth factor activity
- lipid binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- endoplasmic reticulum
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000528157
- Coding exons
- 4
- Length
- 4351
- Individuals with no LoFs
- 124583
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 124596
- p
- 0.0000522
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.672 | 66 | 83.3 | 0.793 | 0.00000437 | 1173 |
| Missense (PolyPhen) | 21 | 42.875 | 0.48979 | 531 | ||
| Synonymous | 0.351 | 28 | 30.5 | 0.919 | 0.00000153 | 349 |
| Loss of Function | 0.714 | 5 | 7.04 | 0.710 | 3.71e-7 | 107 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000065 | 0.000056 | rare |
| Finnish | 0.00023 | 0.00023 | rare |
| European (Non-Finnish) | 0.000028 | 0.000027 | rare |
| South Asian | 0.000068 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain (PubMed:12794311). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (By similarity). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (PubMed:18561914, PubMed:22637475, PubMed:29497057). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475). Following secretion by the ER/SR, directly binds to 3-O- sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (PubMed:29497057). Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions (PubMed:29497057). {ECO:0000250|UniProtKB:P0C5H9, ECO:0000269|PubMed:12794311, ECO:0000269|PubMed:18561914, ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:29497057}.;
Recessive Scores
- pRec
- 0.135
Intolerance Scores
- LoFtool
- 0.303
- RVIS EVS
- -0.01
- RVIS percentile EVS
- 52.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |