ABCB4
ATP binding cassette subfamily B member 4, the group of ATP binding cassette subfamily B
Basic information
Region (hg38): 7:87401695-87480435
Previous symbols: [ "PGY3", "MDR3" ]
Links
Phenotypes
GenCC
Source:
- low phospholipid associated cholelithiasis (Definitive), mode of inheritance: Semidominant
- low phospholipid associated cholelithiasis (Supportive), mode of inheritance: AD
- progressive familial intrahepatic cholestasis type 3 (Supportive), mode of inheritance: AR
- pancreatitis (Limited), mode of inheritance: AD
- low phospholipid associated cholelithiasis (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:
| 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
- not provided (465 variants)
- Progressive familial intrahepatic cholestasis type 3 (117 variants)
- Cholestasis, intrahepatic, of pregnancy, 3 (84 variants)
- not specified (69 variants)
- ABCB4-related condition (28 variants)
- Inborn genetic diseases (22 variants)
- Progressive familial intrahepatic cholestasis type 1 (17 variants)
- Low phospholipid associated cholelithiasis (14 variants)
- Progressive familial intrahepatic cholestasis (8 variants)
- Progressive familial intrahepatic cholestasis type 3;Cholestasis, intrahepatic, of pregnancy, 3;Low phospholipid associated cholelithiasis (3 variants)
- See cases (2 variants)
- Familial intrahepatic cholestasis type 3 (2 variants)
- ABCB4-related disorders (2 variants)
- Progressive familial intrahepatic cholestasis type 3;Low phospholipid associated cholelithiasis;Cholestasis, intrahepatic, of pregnancy, 3 (1 variants)
- Cholestasis, intrahepatic, of pregnancy, 3;Progressive familial intrahepatic cholestasis type 3;Low phospholipid associated cholelithiasis (1 variants)
- ABCB4-Related Intrahepatic Cholestasis (1 variants)
- Cholestasis, intrahepatic, of pregnancy, 3;Low phospholipid associated cholelithiasis (1 variants)
- ABCB4-related disorder (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.
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 | 25 | 47 | 77 | |||
| missense | 19 | 193 | 223 | |||
| nonsense | 26 | 33 | ||||
| start loss | 0 | |||||
| frameshift | 20 | 24 | ||||
| inframe indel | 5 | |||||
| splice donor/acceptor (+/-2bp) | 17 | |||||
| splice region ? | 2 | 17 | 10 | 4 | 33 | |
| non coding ? | 39 | 70 | 114 | |||
| Total | 61 | 37 | 229 | 90 | 76 |
Highest pathogenic variant AF is 0.0000197
Variants in ABCB4
This is a list of pathogenic ClinVar variants found in the ABCB4 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 7-87402098-A-G | Progressive familial intrahepatic cholestasis type 3 | Conflicting classifications of pathogenicity (Jan 01, 2019) | ||
| 7-87402098-A-T | Cholestasis, intrahepatic, of pregnancy, 3 | Likely pathogenic (Mar 17, 2024) | ||
| 7-87402120-G-A | Conflicting classifications of pathogenicity (Mar 29, 2023) | |||
| 7-87402125-T-G | Uncertain significance (Mar 29, 2016) | |||
| 7-87402165-CT-C | Progressive familial intrahepatic cholestasis type 3 | Pathogenic (Jan 01, 2022) | ||
| 7-87402171-C-T | ABCB4-related disorder | Likely benign (Jan 25, 2024) | ||
| 7-87402172-G-A | ABCB4-related disorder | Uncertain significance (Jan 20, 2024) | ||
| 7-87402185-T-G | ABCB4-related disorder | Uncertain significance (Jan 02, 2024) | ||
| 7-87402192-C-T | Likely benign (Dec 08, 2023) | |||
| 7-87402199-T-G | Progressive familial intrahepatic cholestasis type 3 | Uncertain significance (-) | ||
| 7-87402204-C-A | Likely benign (Feb 14, 2023) | |||
| 7-87402211-A-AT | Progressive familial intrahepatic cholestasis type 1 | Pathogenic/Likely pathogenic (May 28, 2019) | ||
| 7-87402231-G-A | ABCB4-related disorder | Likely benign (Jan 12, 2024) | ||
| 7-87402241-C-T | Cholestasis, intrahepatic, of pregnancy, 3 • Progressive familial intrahepatic cholestasis type 3 | Uncertain significance (Jan 13, 2018) | ||
| 7-87402242-G-A | Uncertain significance (Nov 08, 2023) | |||
| 7-87402244-T-C | Uncertain significance (Apr 01, 2022) | |||
| 7-87402256-A-C | Uncertain significance (May 27, 2022) | |||
| 7-87402260-A-C | Inborn genetic diseases | Uncertain significance (Feb 03, 2022) | ||
| 7-87402265-C-T | Inborn genetic diseases | Uncertain significance (Sep 27, 2022) | ||
| 7-87402272-C-T | Uncertain significance (Oct 10, 2016) | |||
| 7-87402277-G-T | not specified | Uncertain significance (May 04, 2022) | ||
| 7-87402285-C-T | Likely benign (Feb 15, 2023) | |||
| 7-87402293-C-T | Inborn genetic diseases | Uncertain significance (Apr 18, 2023) | ||
| 7-87402294-T-C | Likely benign (Jan 20, 2024) | |||
| 7-87402374-A-G | Benign (Jun 29, 2018) |
GnomAD
Source:
| 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:
- 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