CXXC4
protein-codingCXXC finger protein 4, the group of Zinc fingers CXXC-type
Gene summary
This gene encodes a CXXC-type zinc finger domain-containing protein that functions as an antagonist of the canonical wingless/integrated signaling pathway. The encoded protein negatively regulates wingless/integrated signaling through interaction with the post synaptic density protein/ Drosophila disc large tumor suppressor/ zonula occludens-1 protein domain of Dishevelled, a scaffolding protein required for the stabilization of the transcriptional co-activator beta-catenin. In addition, the CXXC domain of this protein has been shown to bind unmethylated CpG dinucleotides, localize to promoters and CpG islands, and interact with the catalytic domain of methylcytosine dioxygenase ten-eleven-translocation 2, an iron and alpha-ketoglutarate-dependent dioxygenase that modifies the methylation status of DNA. In humans, a mutation in this gene has been associated with development of malignant renal cell carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.6 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 CXXC4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025212.4. 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 | 9 | 9 | ||||
| missense | 13 | 13 | ||||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 14 | 9 | 0 | 23 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079488.2 | 2 | MANE Select | |
| Ensembl | ENSP00000378248.2 | 2 | MANE Select | |
| RefSeq | NP_001427581.1 | 2 | Standard | |
| Ensembl | ENSP00000513781.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Wnt signaling pathway - Homo sapiens (human)
- Wnt Signaling Pathway
- Signaling by WNT
- Signal Transduction
- Negative regulation of TCF-dependent signaling by DVL-interacting proteins
Biological Process
- zygotic specification of dorsal/ventral axis
- Wnt signaling pathway
- negative regulation of Wnt signaling pathway
Molecular Function
- DNA binding
- zinc ion binding
- PDZ domain binding
Cellular Component
- cytoplasm
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394767
- Coding exons
- 2
- Length
- 26590
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125733
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.82 | 107 | 175 | 0.613 | 0.00000813 | 2350 |
| Missense (PolyPhen) | 19 | 58.5 | 0.32479 | 710 | ||
| Synonymous | -2.03 | 99 | 76.4 | 1.30 | 0.00000381 | 808 |
| Loss of Function | 2.47 | 0 | 7.13 | 0.00 | 3.04e-7 | 105 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a negative regulator of the Wnt signaling pathway via its interaction with DVL1. {ECO:0000250}.;
Recessive Scores
- pRec
- 0.118
Intolerance Scores
- RVIS EVS
- -0.01
- RVIS percentile EVS
- 52.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.177
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |