CUL4A
protein-codingcullin 4A, the group of Cullins|MicroRNA protein coding host genes
Gene summary
CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009 [PubMed 19481525]).[supplied by OMIM, Oct 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CUL4A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001008895.4. 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 | 2 | ||||
| missense | 70 | 3 | 73 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 78 | 3 | 0 | 81 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001008895.1 | 20 | MANE Select | |
| Ensembl | ENSP00000364589.4 | 20 | MANE Select | |
| RefSeq | NP_001265442.1 | 18 | Standard | |
| RefSeq | NP_001265443.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cul4a | Danio rerio | Structure: pectoral fin Quality: truncated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nucleotide excision repair - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- DNA Repair
- Post-translational protein modification
- Metabolism of proteins
Biological Process
- G1/S transition of mitotic cell cycle
- nucleotide-excision repair, DNA damage recognition
- in utero embryonic development
- transcription-coupled nucleotide-excision repair
- nucleotide-excision repair, preincision complex stabilization
Molecular Function
- protein binding
- ubiquitin protein ligase binding
- ubiquitin protein ligase activity
Cellular Component
- nucleoplasm
- SCF ubiquitin ligase complex
- cullin-RING ubiquitin ligase complex
- Cul4A-RING E3 ubiquitin ligase complex
- Cul4-RING E3 ubiquitin ligase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375440
- Coding exons
- 20
- Length
- 56848
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125745
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.81 | 231 | 386 | 0.598 | 0.0000213 | 5042 |
| Missense (PolyPhen) | 25 | 111.4 | 0.22441 | 1442 | ||
| Synonymous | -1.01 | 169 | 153 | 1.10 | 0.00000959 | 1347 |
| Loss of Function | 5.59 | 1 | 38.3 | 0.0261 | 0.00000169 | 529 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. DCX(DTL) directs autoubiquitination of DTL. {ECO:0000269|PubMed:14578910, ECO:0000269|PubMed:14609952, ECO:0000269|PubMed:15448697, ECO:0000269|PubMed:15548678, ECO:0000269|PubMed:16537899, ECO:0000269|PubMed:16678110, ECO:0000269|PubMed:23478445, ECO:0000269|PubMed:24209620}.;
Recessive Scores
- pRec
- 0.264
Intolerance Scores
- LoFtool
- 0.0395
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.844
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |