APOA5

protein-coding

apolipoprotein A5, the group of Apolipoproteins

Gene summary

The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Oct 2009]

MANE transcript

NM_001371904.1

Inheritance

AD, SD, AR

ClinVar variants

P:33U:190B:106

Top phenotype

Hyperlipoproteinemia, type V

gnomAD constraint

pLI —, LoF o/e 1.03

Max pathogenic AF

—

Genomic locus

chr11:116,789,367-116,792,420

External References & Databases

Ensembl (ENSG00000110243)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypertriglyceridemia 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007788

Submitter: G2P

hyperlipoproteinemia type VSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007762

Submitter: Ambry Genetics

hyperlipoproteinemia type VSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007762

Submitter: PanelApp Australia

hyperlipoproteinemia type VSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007762

Submitter: Genomics England PanelApp

hyperlipoproteinemia type VSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007762

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperlipoproteinemia, type VAD/AR

Manifestation: Cardiovascular; Gastrointestinal

Intervention: Cardiovascular

Rationale: Individuals may have severe hypertriglyceridemia, and interventions related to factors that contribute to cardiovascular sequelae (including through diet and exercise control) may be beneficial, though individuals may develop refractory hypertriglyceridemia

Comments: Variants in additional genes may contribute to phenotypic manifestations

Refs: 16143024; 16200213; 19410254; 19447388; 21993410; 22239554

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to APOA5 variants in ClinVar

11 Conditions Cataloged

Cardiovascular phenotypeTotal: 236

not providedTotal: 169

APOA5-related disorderTotal: 32

not specifiedTotal: 29

Familial type 5 hyperlipoproteinemiaTotal: 14

Hypertriglyceridemia 1Total: 11

Autosomal dominant APOA5-related disordersTotal: 1

HypertriglyceridemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001371904.1. 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 clinvar	88 clinvar		89
missense		2 clinvar	181 clinvar	17 clinvar	1 clinvar	201
nonsense	5 clinvar	10 clinvar	3 clinvar			18
start loss						0
frameshift	3 clinvar	12 clinvar	4 clinvar			19
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	9	24	190	105	1	329

Highest pathogenic variant AF is 0.00017109615

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001371904.1	RefSeq	NP_001358833.1	3	MANE Select
ENST00000227665.9	Ensembl	ENSP00000227665.4	3	MANE Select
NM_001166598.2	RefSeq	NP_001160070.1	3	Standard
NM_052968.5	RefSeq	NP_443200.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PPAR signaling pathway - Homo sapiens (human)
Statin Pathway, Pharmacodynamics
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)
PPAR Alpha Pathway
Nuclear Receptors Meta-Pathway

Biological Process

triglyceride metabolic process
cholesterol biosynthetic process
lipid transport
positive regulation of cholesterol esterification
positive regulation of triglyceride catabolic process

Molecular Function

phospholipid binding
enzyme activator activity
heparin binding
lipid binding
cholesterol binding

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
very-low-density lipoprotein particle
low-density lipoprotein particle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000542499
Coding exons: 3
Length: 3054
Individuals with no LoFs: 125654
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125740
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.861	200	237	0.843	0.0000168	2370
Missense (PolyPhen)		64	79.33	0.80676		812
Synonymous	1.65	81	102	0.792	0.00000764	734
Loss of Function	-0.102	14	13.6	1.03	6.90e-7	130

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00037	0.00036	rare
South Asian	0.00033	0.00033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL. May also be associated with chylomicrons. Important determinant of plasma triglyceride (TG) levels by both being a potent stimulator of apo-CII lipoprotein lipase (LPL) TG hydrolysis and a inhibitor of the hepatic VLDL-TG production rate (without affecting the VLDL-apoB production rate) (By similarity). Activates poorly lecithin:cholesterol acyltransferase (LCAT) and does not enhance efflux of cholesterol from macrophages. {ECO:0000250, ECO:0000269|PubMed:11588264, ECO:0000269|PubMed:12899628, ECO:0000269|PubMed:15528295}.;
Disease: DISEASE: Hypertriglyceridemia, familial (FHTR) [MIM:145750]: A common inherited disorder in which the concentration of very low density lipoprotein (VLDL) is elevated in the plasma. This leads to increased risk of heart disease, obesity, and pancreatitis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hyperlipoproteinemia 5 (HLPP5) [MIM:144650]: Characterized by increased amounts of chylomicrons and very low density lipoprotein (VLDL) and decreased low density lipoprotein (LDL) and high density lipoprotein (HDL) in the plasma after a fast. Numerous conditions cause this phenotype, including insulin- dependent diabetes mellitus, contraceptive steroids, alcohol abuse, and glycogen storage disease type 1A (GSD1A). {ECO:0000269|PubMed:16200213}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.357

Intolerance Scores

LoFtool: 0.927
RVIS EVS: 0.42
RVIS percentile EVS: 77.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.304

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium