ANGPTL4
protein-codingangiopoietin like 4, the group of Angiopoietin like family|Fibrinogen C domain containing
Gene summary
This gene encodes a glycosylated, secreted protein containing a C-terminal fibrinogen domain. The encoded protein is induced by peroxisome proliferation activators and functions as a serum hormone that regulates glucose homeostasis, lipid metabolism, and insulin sensitivity. This protein can also act as an apoptosis survival factor for vascular endothelial cells and can prevent metastasis by inhibiting vascular growth and tumor cell invasion. The C-terminal domain may be proteolytically-cleaved from the full-length secreted protein. Decreased expression of this gene has been associated with type 2 diabetes. Alternative splicing results in multiple transcript variants. This gene was previously referred to as ANGPTL2 but has been renamed ANGPTL4. [provided by RefSeq, Sep 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.1 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 ANGPTL4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_139314.3. 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 | 4 | 3 | 7 | |||
| missense | 43 | 4 | 1 | 48 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 48 | 8 | 4 | 60 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_647475.1 | 7 | MANE Select | |
| Ensembl | ENSP00000301455.1 | 7 | MANE Select | |
| RefSeq | NP_001034756.1 | 6 | Standard | |
| Ensembl | ENSP00000377534.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| angptl4 | Danio rerio | Structure: endothelial cell Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cholesterol metabolism - Homo sapiens (human)
- PPAR signaling pathway - Homo sapiens (human)
- Transcriptional regulation of white adipocyte differentiation
- Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
- Glucocorticoid Receptor Pathway
Biological Process
- angiogenesis
- response to hypoxia
- regulation of lipid metabolic process
- cell differentiation
- negative regulation of apoptotic process
Molecular Function
- enzyme inhibitor activity
- protein binding
- identical protein binding
Cellular Component
- extracellular region
- extracellular space
- blood microparticle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000301455
- Coding exons
- 7
- Length
- 11085
- Individuals with no LoFs
- 125636
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 112
- Defined
- 125748
- p
- 0.000445
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.439 | 227 | 246 | 0.921 | 0.0000151 | 2610 |
| Missense (PolyPhen) | 98 | 99.459 | 0.98533 | 1127 | ||
| Synonymous | 0.601 | 98 | 106 | 0.926 | 0.00000628 | 809 |
| Loss of Function | 0.570 | 18 | 20.8 | 0.865 | 0.00000118 | 185 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00024 | 0.00023 | rare |
| Ashkenazi Jewish | 0.0012 | 0.0012 | notable |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00043 | 0.00042 | rare |
| European (Non-Finnish) | 0.00064 | 0.00063 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Protein with hypoxia-induced expression in endothelial cells. May act as a regulator of angiogenesis and modulate tumorigenesis. Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage. May exert a protective function on endothelial cells through an endocrine action. It is directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. In response to hypoxia, the unprocessed form of the protein accumulates in the subendothelial extracellular matrix (ECM). The matrix-associated and immobilized unprocessed form limits the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibits their adhesion. It also decreases motility of endothelial cells and inhibits the sprouting and tube formation (By similarity). {ECO:0000250, ECO:0000269|PubMed:12015030, ECO:0000269|PubMed:14583458}.;
Intolerance Scores
- LoFtool
- 0.837
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.91
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.382
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |