AKR1C4
protein-codingaldo-keto reductase family 1 member C4, the group of Aldo-keto reductases
Gene summary
This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]
- CHDR
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013664
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013664
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AKR1C4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001818.5. 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 | 2 | 17 | 19 | |||
| missense | 62 | 8 | 2 | 72 | ||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 68 | 25 | 2 | 95 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001809.4 | 9 | MANE Select | |
| Ensembl | ENSP00000263126.1 | 9 | MANE Select | |
| Ensembl | ENSP00000369814.1 | 9 | Standard | |
| Ensembl | ENSP00000571669.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Steroid hormone biosynthesis - Homo sapiens (human)
- Primary bile acid biosynthesis - Homo sapiens (human)
- 27-Hydroxylase Deficiency
- Bile Acid Biosynthesis
- Steroidogenesis
Biological Process
- retinoid metabolic process
- prostaglandin metabolic process
- bile acid biosynthetic process
- steroid metabolic process
- androgen metabolic process
Molecular Function
- retinal dehydrogenase activity
- alditol:NADP+ 1-oxidoreductase activity
- aldo-keto reductase (NADP) activity
- alcohol dehydrogenase (NADP+) activity
- electron transfer activity
Cellular Component
- cytoplasm
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000380448
- Coding exons
- 9
- Length
- 23488
- Individuals with no LoFs
- 125645
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 100
- Defined
- 125745
- p
- 0.000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.04 | 214 | 175 | 1.22 | 0.00000892 | 2108 |
| Missense (PolyPhen) | 84 | 73.641 | 1.1407 | 912 | ||
| Synonymous | -0.951 | 73 | 63.4 | 1.15 | 0.00000309 | 601 |
| Loss of Function | -0.916 | 23 | 18.7 | 1.23 | 9.74e-7 | 219 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00020 | rare |
| East Asian | 0.00054 | 0.00054 | rare |
| Finnish | 0.0011 | 0.0011 | notable |
| European (Non-Finnish) | 0.00034 | 0.00033 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha- androstan-3-alpha,17-beta-diol (3-alpha-diol). Also has some 20- alpha-hydroxysteroid dehydrogenase activity. The biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leads to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route.;
- Disease
- DISEASE: 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The gene represented in this entry may act as a disease modifier. A splicing mutation resulting in loss of AKR1C4 exon 2 has been found in affected individuals carrying a causative mutation in AKR1C2 (PubMed:21802064). These patients manifest a more severe disease phenotype than individuals only carrying mutations in AKR1C2. {ECO:0000269|PubMed:21802064}.;
Recessive Scores
- pRec
- 0.154
Intolerance Scores
- LoFtool
- 0.903
- RVIS EVS
- 0
- RVIS percentile EVS
- 53.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.334
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |