ANGPTL3
angiopoietin like 3, the group of Angiopoietin like family|Receptor ligands|Fibrinogen C domain containing
Basic information
Region (hg38): 1:62597520-62606313
Previous symbols: [ "ANGPT5" ]
Links
Phenotypes
GenCC
Source:
- familial hypobetalipoproteinemia 2 (Moderate), mode of inheritance: AR
- familial hypobetalipoproteinemia 2 (Strong), mode of inheritance: AR
- familial hypobetalipoproteinemia 2 (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Hypobetalipoproteinemia, familial, 2 | AR | General | 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 | Gastrointestinal | 9508071; 9508071; 20942659; 22659251 |
| Unlike hypobetalipoproteinemia due to variants in APOB, individuals with variants in ANGPTL3 do not appear to to have increased susceptibility to hepatic steatosis or gastrointestinal or cardiovascular manifestations compared to unaffected relatives; Heterozygous individuals may demonstrate laboratory-based manifestations (eg, lower plasma LDL and triglycerides) |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (75 variants)
- Inborn_genetic_diseases (43 variants)
- Familial_hypobetalipoproteinemia_2 (11 variants)
- Developmental_and_epileptic_encephalopathy,_23 (10 variants)
- ANGPTL3-related_disorder (4 variants)
- DOCK7-related_disorder (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the ANGPTL3 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000014495.4. Only rare variants are included in the table.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 25 | 27 | ||||
| missense | 56 | 65 | ||||
| nonsense | 3 | |||||
| start loss | 0 | |||||
| frameshift | 6 | |||||
| splice donor/acceptor (+/-2bp) | 4 | |||||
| Total | 10 | 2 | 57 | 33 | 3 |
Highest pathogenic variant AF is 0.000434698
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| ANGPTL3 | protein_coding | protein_coding | ENST00000371129 | 7 | 8673 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.65e-13 | 0.0540 | 125547 | 0 | 179 | 125726 | 0.000712 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.0942 | 232 | 228 | 1.02 | 0.0000106 | 3042 |
| Missense in Polyphen | 68 | 58.835 | 1.1558 | 809 | ||
| Synonymous | -0.631 | 91 | 83.7 | 1.09 | 0.00000437 | 809 |
| Loss of Function | 0.432 | 21 | 23.2 | 0.903 | 0.00000115 | 293 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00301 | 0.00300 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000447 | 0.000435 |
| Finnish | 0.000101 | 0.0000924 |
| European (Non-Finnish) | 0.000840 | 0.000756 |
| Middle Eastern | 0.000447 | 0.000435 |
| South Asian | 0.000777 | 0.000686 |
| Other | 0.00124 | 0.00114 |
dbNSFP
Source:
- Function
- FUNCTION: Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity). {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11788823, ECO:0000269|PubMed:12097324, ECO:0000269|PubMed:12565906, ECO:0000269|PubMed:12909640, ECO:0000269|PubMed:17110602, ECO:0000269|PubMed:19028676, ECO:0000269|PubMed:19318355, ECO:0000269|PubMed:20581395, ECO:0000269|PubMed:23661675, ECO:0000269|PubMed:25495645, ECO:0000305|PubMed:20581395}.; FUNCTION: Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity). {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11877390, ECO:0000269|PubMed:18535744}.;
- Disease
- DISEASE: Hypobetalipoproteinemia, familial, 2 (FHBL2) [MIM:605019]: A disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Affected individuals present with combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides. {ECO:0000269|PubMed:20942659}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness. {ECO:0000305|PubMed:17191020}.; DISEASE: Note=May be involved in nephrotic syndrome. {ECO:0000305|PubMed:25710887}.;
- Pathway
- Cholesterol metabolism - Homo sapiens (human);Transport of small molecules;Assembly of active LPL and LIPC lipase complexes;Plasma lipoprotein assembly, remodeling, and clearance;Plasma lipoprotein remodeling;Integrins in angiogenesis
(Consensus)
Intolerance Scores
- loftool
- 0.869
- rvis_EVS
- -0.11
- rvis_percentile_EVS
- 45.26
Haploinsufficiency Scores
- pHI
- 0.611
- hipred
- N
- hipred_score
- 0.339
- ghis
- 0.397
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- N
- gene_indispensability_score
- 0.0141
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Angptl3
- Phenotype
- homeostasis/metabolism phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); liver/biliary system phenotype;
Zebrafish Information Network
- Gene name
- angptl3
- Affected structure
- intestine
- Phenotype tag
- abnormal
- Phenotype quality
- decreased amount
Gene ontology
- Biological process
- angiogenesis;glycerol metabolic process;fatty acid metabolic process;phospholipid metabolic process;cell-matrix adhesion;signal transduction;integrin-mediated signaling pathway;cholesterol metabolic process;phospholipid catabolic process;response to hormone;regulation of signaling receptor activity;negative regulation of phospholipase activity;lipid storage;positive regulation of cell migration;cholesterol homeostasis;positive regulation of angiogenesis;artery morphogenesis;positive regulation of lipid catabolic process;regulation of lipoprotein lipase activity;negative regulation of lipoprotein lipase activity;lipid homeostasis;acylglycerol homeostasis;phospholipid homeostasis;triglyceride homeostasis
- Cellular component
- extracellular region;extracellular space;early endosome;Golgi apparatus;cell surface;lamellipodium
- Molecular function
- enzyme inhibitor activity;phospholipase inhibitor activity;integrin binding;growth factor activity;heparin binding