KLF11
protein-codingKLF transcription factor 11, the group of Kruppel like factors|Zinc fingers C2H2-type
Gene summary
The protein encoded by this gene is a zinc finger transcription factor that binds to SP1-like sequences in epsilon- and gamma-globin gene promoters. This binding inhibits cell growth and causes apoptosis. Defects in this gene are a cause of maturity-onset diabetes of the young type 7 (MODY7). Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]
- TIEG2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
Evidence asserting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of case-level and experimental data: 1.5 points. *KLF11 *was first reported in relation to autosomal dominant monogenic diabetes in 2005 (Neve et al., 2005, PMID: 15774581). One of the original variants reported, p.Thr220Met (rs34336420), is now known to have a MAF of 0.04 in Africans (gnomAD) and is classified as benign/likely benign in ClinVar, and the second one p.Ala347Ser (rs121912645) has MAFs of 0.0005 and 0.0001 in Latino and European populations respectively. A common variant p.Gln62Arg (rs35927125, MAF in Europeans 0.12) was modestly associated with T2D in the original publication, but this is not borne out in the AMP T2D Portal (ExTexT2D exome chip Pval 0.08; type2diabetesgenetics.org). A rare variant (p.His418Gln) in this gene segregated with antibody negative childhood onset diabetes in 3 family members; a fourth carrier was said to be unaffected with limited information available (PMID: 31124255), reducing evidence for segregation. A rare variant (p.Pro193Thr) was found in a father and son with early onset (32 and 13 years) diabetes with metabolic syndrome features (PMID: 36241199). Variants have shown in vitro effects on transcription and/or cofactor binding (PMIDs: 15774581, 31124255, 36241199). Laver et al (PMID: 35108381) reported a lack of enrichment of ultra-rare (MAF<6x10-6) protein-truncating and missense variants in *BLK*, *PAX4*, and *KLF11* in a large cohort of cases with suspected MODY (n=1227) compared to population cohort (UK Biobank =185,898), gnomADv2 and gnomADv3. They also showed a similar lack of enrichment of protein-truncating variants of any frequency in *BLK*, *PAX4*, and *KLF11* in the MODY cohort. In summary, there is limited evidence to support, and there appears to be strong evidence to contradict the *KLF11*-monogenic diabetes relationship that warrants refuting the association (originally asserted as maturity-onset diabetes of the young 7, MODY7, MIM: 610508).
Inheritance Pattern: AD
Disease ID:MONDO:0012513
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012513
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KLF11 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003597.5. 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 | 5 | 54 | 2 | 61 | ||
| missense | 168 | 28 | 1 | 197 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 177 | 82 | 3 | 262 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003588.1 | 4 | MANE Select | |
| Ensembl | ENSP00000307023.1 | 4 | MANE Select | |
| RefSeq | NP_001171187.1 | 3 | Standard | |
| RefSeq | NP_001171189.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- B Cell Receptor Signaling Pathway
- TGF-beta Signaling Pathway
- EGFR1
Biological Process
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- negative regulation of transcription by RNA polymerase II
- regulation of transcription by RNA polymerase II
- transcription by RNA polymerase II
- apoptotic process
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
- transcription regulatory region DNA binding
- metal ion binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- focal adhesion
- nuclear body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000305883
- Coding exons
- 4
- Length
- 11988
- Individuals with no LoFs
- 125697
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 125748
- p
- 0.000203
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.50 | 362 | 290 | 1.25 | 0.0000170 | 3314 |
| Missense (PolyPhen) | 90 | 90.995 | 0.98907 | 988 | ||
| Synonymous | -3.20 | 160 | 116 | 1.38 | 0.00000695 | 1090 |
| Loss of Function | 0.253 | 13 | 14.0 | 0.927 | 8.90e-7 | 168 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00018 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00099 | 0.00099 | rare |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000094 | 0.000092 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor (PubMed:9748269, PubMed:10207080). Activates the epsilon- and gamma-globin gene promoters and, to a much lower degree, the beta-globin gene and represses promoters containing SP1-like binding inhibiting cell growth (PubMed:9748269, PubMed:10207080, PubMed:16131492). Represses transcription of SMAD7 which enhances TGF-beta signaling (By similarity). Induces apoptosis (By similarity). {ECO:0000250|UniProtKB:Q8K1S5, ECO:0000269|PubMed:10207080, ECO:0000269|PubMed:16131492}.;
- Disease
- DISEASE: Maturity-onset diabetes of the young 7 (MODY7) [MIM:610508]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:15774581}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.130
Intolerance Scores
- LoFtool
- 0.815
- RVIS EVS
- 0.25
- RVIS percentile EVS
- 69.57
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 |