KLF4
protein-codingKLF transcription factor 4, the group of Kruppel like factors|Zinc fingers C2H2-type
Gene summary
This gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required for normal development of the barrier function of skin. The encoded protein is thought to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. Mice lacking this gene have a normal appearance but lose weight rapidly, and die shortly after birth due to fluid evaporation resulting from compromised epidermal barrier function. Alternative splicing results in multiple transcript variants encoding different isoforms. [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 ~5.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019272
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019268
Submitter: Ambry Genetics
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KLF4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004235.6. 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 | 1 | 6 | 6 | 13 | ||
| missense | 82 | 6 | 88 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 84 | 12 | 6 | 102 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004226.3 | 5 | MANE Select | |
| Ensembl | ENSP00000363804.4 | 5 | MANE Select | |
| RefSeq | NP_001300981.1 | 4 | Standard | |
| Ensembl | ENSP00000404922.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| klf4 | Danio rerio | Structure: goblet cell Quality: poorly differentiated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- SRF and miRs in Smooth Muscle Differentiation and Proliferation
- Cell Differentiation - Index expanded
- White fat cell differentiation
- Mesodermal Commitment Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- regulation of transcription by RNA polymerase II
- transcription by RNA polymerase II
- mesodermal cell fate determination
- negative regulation of cell population proliferation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- proximal promoter sequence-specific DNA binding
- RNA polymerase II sequence-specific DNA-binding transcription factor recruiting activity
- RNA polymerase II transcription factor binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- nuclear euchromatin
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374672
- Coding exons
- 5
- Length
- 5631
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.100 | 275 | 280 | 0.983 | 0.0000147 | 3020 |
| Missense (PolyPhen) | 127 | 143.63 | 0.88421 | 1537 | ||
| Synonymous | -2.43 | 163 | 128 | 1.27 | 0.00000749 | 1025 |
| Loss of Function | 3.84 | 0 | 17.2 | 0.00 | 9.43e-7 | 177 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| 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 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor; can act both as activator and as repressor. Binds the 5'-CACCC-3' core sequence. Binds to the promoter region of its own gene and can activate its own transcription. Regulates the expression of key transcription factors during embryonic development. Plays an important role in maintaining embryonic stem cells, and in preventing their differentiation. Required for establishing the barrier function of the skin and for postnatal maturation and maintenance of the ocular surface. Involved in the differentiation of epithelial cells and may also function in skeletal and kidney development. Contributes to the down-regulation of p53/TP53 transcription. {ECO:0000269|PubMed:17308127, ECO:0000269|PubMed:20071344}.;
Recessive Scores
- pRec
- 0.408
Intolerance Scores
- RVIS EVS
- -0.45
- RVIS percentile EVS
- 24.19
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.956
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |