ABCB4

ATP binding cassette subfamily B member 4, the group of ATP binding cassette subfamily B

Basic information

Region (hg38): 7:87401696-87480435

Previous symbols: [ "PGY3", "MDR3" ]

Links

ENSG00000005471

∙ NCBI:5244 ∙ OMIM:171060 ∙ HGNC:45 ∙ Uniprot:P21439 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

gallbladder disease 1 (Definitive), mode of inheritance: Semidominant
gallbladder disease 1 (Supportive), mode of inheritance: AD
progressive familial intrahepatic cholestasis type 3 (Supportive), mode of inheritance: AR
pancreatitis (Limited), mode of inheritance: AD
gallbladder disease 1 (Strong), mode of inheritance: AD
progressive familial intrahepatic cholestasis type 3 (Strong), mode of inheritance: AR
progressive familial intrahepatic cholestasis type 3 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cholestasis, progressive familial intrahepatic 3; Gallbladder disease 1; Cholestasis, familial intrahepatic, of pregnancy, 3	AD/AR	Gastrointestinal; Obstetric; Pharmacogenomic	Medical treatment (eg, with ursodeoxycholine) may be beneficial, though in some forms, liver transplantation has been described as necessary; Medications (eg, OCPs) may lead to adverse reactions; In pregnancy, the condition can cause severe sequelae (including death) in the fetus, as well as adverse maternal health outcomes, and precautions, including early delivery, may be beneficial	Gastrointestinal	8666348; 9049190; 9419367; 9923886; 10767346; 11313315; 11313316; 15203080; 17726488; 17414143; 18482588; 19584064; 20887599; 20537830; 21310683; 21119540; 21989363
Heterozygous variants reported in Cholestasis, progressive familial intrahepatic 3 are associated with other related conditions such as Intrahepatic cholestasis of pregnancy

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCB4 gene.

not_provided (766 variants)
Progressive_familial_intrahepatic_cholestasis_type_3 (152 variants)
ABCB4-related_disorder (151 variants)
Cholestasis,_intrahepatic,_of_pregnancy,_3 (132 variants)
not_specified (99 variants)
Inborn_genetic_diseases (84 variants)
Low_phospholipid_associated_cholelithiasis (50 variants)
Progressive_familial_intrahepatic_cholestasis_type_1 (17 variants)
Progressive_familial_intrahepatic_cholestasis (12 variants)
Familial_intrahepatic_cholestasis_type_3 (2 variants)
ABCB4-Related_Intrahepatic_Cholestasis (2 variants)
See_cases (2 variants)
Schizophrenia (1 variants)
Intrahepatic_cholestasis (1 variants)
Severe_early-childhood-onset_retinal_dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCB4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000443.4. 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	2 clinvar		14 clinvar	257 clinvar	3 clinvar	276
missense	6 clinvar	45 clinvar	337 clinvar	9 clinvar	2 clinvar	399
nonsense	31 clinvar	13 clinvar	1 clinvar			45
start loss		1				1
frameshift	33 clinvar	14 clinvar				47
splice donor/acceptor (+/-2bp)	10 clinvar	24 clinvar	1 clinvar			35
Total	82	97	353	266	5

Highest pathogenic variant AF is 0.0011865061

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCB4	protein_coding	protein_coding	ENST00000265723	27	78739

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.21e-7	1.00	125690	0	58	125748	0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.97	539	684	0.788	0.0000365	8409
Missense in Polyphen		131	222.79	0.588		2707
Synonymous	0.828	243	260	0.935	0.0000150	2536
Loss of Function	4.82	24	66.4	0.361	0.00000370	785

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000819	0.000811
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000383	0.000381
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000150	0.000149
Middle Eastern	0.000383	0.000381
South Asian	0.000327	0.000327
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

Function: FUNCTION: Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts (PubMed:7957936, PubMed:8898203, PubMed:9366571, PubMed:17523162, PubMed:23468132, PubMed:24806754, PubMed:24723470, PubMed:24594635, PubMed:21820390). Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to fu rther enrichment of SM and cholesterol in raft membranes in hepatocytes (PubMed:23468132). Required for proper phospholipid bile formation (By similarity). Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP- dependent manner (PubMed:24045840). Promotes biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane (PubMed:9366571, PubMed:28012258). In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts (PubMed:21820390). Does not confer multidrug resistance (By similarity). {ECO:0000250|UniProtKB:P21440, ECO:0000269|PubMed:17523162, ECO:0000269|PubMed:21820390, ECO:0000269|PubMed:23468132, ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:24806754, ECO:0000269|PubMed:28012258, ECO:0000269|PubMed:7957936, ECO:0000269|PubMed:8898203, ECO:0000269|PubMed:9366571}.;
Disease: DISEASE: Cholestasis, progressive familial intrahepatic, 3 (PFIC3) [MIM:602347]: A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. {ECO:0000269|PubMed:11313315, ECO:0000269|PubMed:12671900, ECO:0000269|PubMed:17726488, ECO:0000269|PubMed:21119540, ECO:0000269|PubMed:24045840, ECO:0000269|PubMed:24594635, ECO:0000269|PubMed:24806754, ECO:0000269|PubMed:28012258, ECO:0000269|PubMed:9419367}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cholestasis of pregnancy, intrahepatic 3 (ICP3) [MIM:614972]: A liver disorder of pregnancy. It presents during the second or, more commonly, the third trimester of pregnancy with intense pruritus which becomes more severe with advancing gestation and cholestasis. It causes fetal distress, spontaneous premature delivery and intrauterine death. Patients have spontaneous and progressive disappearance of cholestasis after delivery. Cholestasis results from abnormal biliary transport from the liver into the small intestine. {ECO:0000269|PubMed:10767346, ECO:0000269|PubMed:12746424, ECO:0000269|PubMed:15077010}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gallbladder disease 1 (GBD1) [MIM:600803]: One of the major digestive diseases. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations in western countries. Most people with gallstones, however, remain asymptomatic through their lifetimes. {ECO:0000269|PubMed:11313316, ECO:0000269|PubMed:12891548, ECO:0000269|PubMed:22331132, ECO:0000269|PubMed:23533021, ECO:0000269|PubMed:24723470, ECO:0000269|PubMed:28012258, ECO:0000269|Ref.2}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: Bile secretion - Homo sapiens (human);ABC transporters - Homo sapiens (human);Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha);Farnesoid X Receptor Pathway;Nuclear Receptors Meta-Pathway;Nuclear Receptors in Lipid Metabolism and Toxicity;multi-drug resistance factors;Transport of small molecules;ABC-family proteins mediated transport;Arachidonic acid metabolism (Consensus)

Recessive Scores

pRec: 0.407

Intolerance Scores

loftool: 0.0172
rvis_EVS: -0.55
rvis_percentile_EVS: 20.02

Haploinsufficiency Scores

pHI: 0.0848
hipred: N
hipred_score: 0.431
ghis: 0.444

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.135

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Abcb4
Phenotype: liver/biliary system phenotype; neoplasm; reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); digestive/alimentary phenotype; skeleton phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype;

Zebrafish Information Network

Gene name: abcb4
Affected structure: efflux transmembrane transporter activity
Phenotype tag: abnormal
Phenotype quality: decreased process quality

Gene ontology

Biological process: lipid metabolic process;regulation of lipid metabolic process;positive regulation of cholesterol transport;bile acid secretion;response to drug;phospholipid translocation;transmembrane transport;lipid homeostasis;positive regulation of phospholipid translocation;ceramide translocation;response to fenofibrate;cellular response to bile acid;positive regulation of phospholipid transport
Cellular component: nucleoplasm;cytoplasm;cytosol;plasma membrane;integral component of plasma membrane;focal adhesion;actin cytoskeleton;membrane;apical plasma membrane;clathrin-coated vesicle;membrane raft;intercellular canaliculus;extracellular exosome
Molecular function: protein binding;ATP binding;phospholipid transporter activity;phosphatidylcholine transporter activity;ATPase activity, coupled to transmembrane movement of substances;phosphatidylcholine-translocating ATPase activity;ceramide-translocating ATPase activity