ABCC4
protein-codingATP binding cassette subfamily C member 4, the group of ATP binding cassette subfamily C
Gene summary
The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This family member plays a role in cellular detoxification as a pump for its substrate, organic anions. It may also function in prostaglandin-mediated cAMP signaling in ciliogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~281.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0001197
Submitter: ClinGen
ABCC4 was first reported in relation to an autosomal recessive qualitative platelet defect in 2020 (Azouzi S, et al., 2020, PMID: 31826245). This heritable platelet function defect is characterized by reduced platelet aggregation in response to low concentration ADP. ABCC4 encodes MRP4 which is thought to promote platelet aggregation by modulating the cAMP–protein kinase A signaling pathway. One variant (the GRCh38 (chr13:95018454-95085982) deletion accompanied by the insertion of an intervening 18-bp sequence of CTGTAATCCCAGCACTTT) has been reported in 4 French-Canadian probands in 1 publication (PMID: 31826245). This gene-disease association is supported by its function in cAMP transport (PMID: 11856762), which when disrupted leads to a platelet aggregation defect (PMID: 35295075), as well as its expression on the plasma membrane of platelets (PMID: 26405223), and two mouse models that recapitulate a platelet aggregation defect (PMIDs: 26405223, 26316625). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was previously evaluated by the HT GCEP on May 25, 2022. It was reevaluated on June 3, 2024. As a result of this reevaluation no new evidence was identified and the classification remained Moderate (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABCC4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005845.5. 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 | 3 | 11 | 5 | 19 | ||
| missense | 145 | 9 | 4 | 158 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 0 | 152 | 20 | 9 | 181 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005836.2 | 31 | MANE Select | |
| Ensembl | ENSP00000494609.1 | 31 | MANE Select | |
| RefSeq | NP_001098985.1 | 21 | Standard | |
| RefSeq | NP_001288758.1 | 30 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| abcc4 | Danio rerio | Structure: post-vent region Quality: curved ventral abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Methotrexate Pathway (Brain Cell), Pharmacokinetics
- Bile secretion - Homo sapiens (human)
- ABC transporters - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
- Fluoropyrimidine Pathway, Pharmacokinetics
Biological Process
- platelet degranulation
- biological_process
- response to organonitrogen compound
- response to organic cyclic compound
- prostaglandin secretion
Molecular Function
- ATP binding
- ATPase activity, coupled to transmembrane movement of ions, phosphorylative mechanism
- 15-hydroxyprostaglandin dehydrogenase (NAD+) activity
- ATPase activity, coupled to transmembrane movement of substances
- ATPase-coupled anion transmembrane transporter activity
Cellular Component
- plasma membrane
- membrane
- integral component of membrane
- basolateral plasma membrane
- platelet dense granule membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000376887
- Coding exons
- 31
- Length
- 281605
- Individuals with no LoFs
- 125606
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 142
- Defined
- 125748
- p
- 0.000565
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.70 | 591 | 719 | 0.821 | 0.0000397 | 8587 |
| Missense (PolyPhen) | 146 | 221.97 | 0.65773 | 2720 | ||
| Synonymous | -0.746 | 294 | 278 | 1.06 | 0.0000169 | 2581 |
| Loss of Function | 5.12 | 26 | 73.3 | 0.355 | 0.00000355 | 913 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00022 | 0.00016 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00089 | 0.00086 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be an organic anion pump relevant to cellular detoxification.;
Recessive Scores
- pRec
- 0.370
Intolerance Scores
- LoFtool
- 0.0441
- RVIS EVS
- 0.21
- RVIS percentile EVS
- 67.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.735
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |