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

ENSG00000132855 ∙ NCBI:27329 ∙ OMIM:604774 ∙ HGNC:491 ∙ Uniprot:Q9Y5C1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the ANGPTL3 gene.

• not provided (2 variants)
• Developmental and epileptic encephalopathy, 23 (1 variants)
• ANGPTL3-related disorder (1 variants)
• Inborn genetic diseases (1 variants)
• Familial hypobetalipoproteinemia 2 (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				17	2	19
missense			43	4	1	48
nonsense			1			1
start loss						0
frameshift	3					3
inframe indel			2			2
splice donor/acceptor (+/-2bp)		1		1		2
splice region			1	2		3
non coding				12	5	17
Total	3	1	46	34	8

Highest pathogenic variant AF is 0.000388

Variants in ANGPTL3

This is a list of pathogenic ClinVar variants found in the ANGPTL3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-62597553-A-C			Likely benign (Apr 08, 2021)
1-62597584-CCTT-C			Uncertain significance (Oct 17, 2022)
1-62597606-G-C		Inborn genetic diseases	Uncertain significance (Feb 21, 2024)
1-62597608-T-G			Likely benign (Dec 01, 2022)
1-62597611-T-C			Likely benign (May 08, 2024)
1-62597616-CC-GA		Familial hypobetalipoproteinemia 2	Pathogenic (Jul 01, 2012)
1-62597619-GA-G		Familial hypobetalipoproteinemia 2	Pathogenic (Feb 01, 2012)
1-62597629-A-C		Inborn genetic diseases	Uncertain significance (Mar 01, 2023)
1-62597635-T-C		ANGPTL3-related disorder	Likely benign (Nov 23, 2020)
1-62597637-C-T		Inborn genetic diseases	Uncertain significance (Dec 27, 2023)
1-62597639-T-C			Uncertain significance (Jun 22, 2022)
1-62597643-T-G		Inborn genetic diseases	Uncertain significance (Aug 14, 2024)
1-62597651-C-T			Likely benign (Nov 01, 2024)
1-62597773-T-C			Likely benign (Jan 22, 2024)
1-62597783-C-A		Inborn genetic diseases	Uncertain significance (Jul 15, 2021)
1-62597794-C-G		Developmental and epileptic encephalopathy, 23	Benign/Likely benign (Oct 01, 2024)
1-62597809-T-C			Likely benign (Jan 04, 2024)
1-62597823-C-T		Inborn genetic diseases	Uncertain significance (Jun 19, 2024)
1-62597838-A-G			Uncertain significance (Jun 01, 2022)
1-62597843-AAAG-A		Familial hypobetalipoproteinemia 2 • Developmental and epileptic encephalopathy, 23	Uncertain significance (Apr 11, 2023)
1-62597857-G-T		Inborn genetic diseases	Uncertain significance (Sep 25, 2023)
1-62597871-C-T		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
1-62597915-T-G		Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
1-62597918-C-T			Uncertain significance (Jul 26, 2022)
1-62597921-GAACTC-G		Familial hypobetalipoproteinemia 2 • Developmental and epileptic encephalopathy, 23 • ANGPTL3-related disorder	Pathogenic (Sep 11, 2023)

GnomAD

Source: gnomAD

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: dbNSFP

• 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