HNF1A
protein-codingHNF1 homeobox A, the group of HNF class homeoboxes
Gene summary
The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
- MODY3
- TCF1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0010894
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012919
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007455
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012919
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0015967
Submitter: ClinGen
Inheritance Pattern: Unknown
Disease ID:MONDO:0007763
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010894
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010894
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018911
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017935
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Oncologic
Intervention: Endocrine; Oncologic
Rationale: Surveillance and early detection of and treatment for neoplasms (eg, including renal and/or hepatic neoplasms) may decrease morbidity and mortality; Individuals with Maturity onset diabetes of the young, type 3 have been reported as presenting in childhood with macrosomia and hyperinsulinism, which has been reported as diazoxide-responsive
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HNF1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000545.8. 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 | 3 | 7 | 178 | 7 | 197 |
| missense | 53 | 104 | 354 | 30 | 19 | 560 |
| nonsense | 41 | 19 | 1 | 1 | 62 | |
| start loss | 3 | 2 | 5 | |||
| frameshift | 79 | 59 | 7 | 145 | ||
| splice donor/acceptor (+/-2bp) | 21 | 22 | 3 | 46 | ||
| Total | 199 | 209 | 372 | 209 | 26 | 1015 |
Highest pathogenic variant AF is 0.00009528586
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000536.6 | 10 | MANE Select | |
| Ensembl | ENSP00000257555.5 | 10 | MANE Select | |
| RefSeq | NP_001293108.2 | 10 | Standard | |
| RefSeq | NP_001393844.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hnf1a | Danio rerio | Structure: pancreatic B cell Quality: decreased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Maturity onset diabetes of the young - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
- WNT-Core
- Adipogenesis
Biological Process
- natural killer cell differentiation
- liver development
- regulation of transcription by RNA polymerase II
- insulin secretion
- pancreas development
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
- protein binding
Cellular Component
- nucleus
- cytoplasm
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000257555
- Coding exons
- 10
- Length
- 23970
- Individuals with no LoFs
- 125710
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125718
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.14 | 318 | 380 | 0.836 | 0.0000240 | 4043 |
| Missense (PolyPhen) | 80 | 114.45 | 0.69898 | 1266 | ||
| Synonymous | -1.42 | 201 | 177 | 1.14 | 0.0000124 | 1361 |
| Loss of Function | 4.18 | 4 | 27.8 | 0.144 | 0.00000154 | 278 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000047 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver. Required for the expression of several liver specific genes. Binds to the inverted palindrome 5'- GTTAATNATTAAC-3'. {ECO:0000269|PubMed:10966642, ECO:0000269|PubMed:12453420}.;
- Disease
- DISEASE: Hepatic adenomas familial (HEPAF) [MIM:142330]: Rare benign liver tumors of presumable epithelial origin that develop in an otherwise normal liver. Hepatic adenomas may be single or multiple. They consist of sheets of well-differentiated hepatocytes that contain fat and glycogen and can produce bile. Bile ducts or portal areas are absent. Kupffer cells, if present, are reduced in number and are non-functional. Conditions associated with adenomas are insulin-dependent diabetes mellitus and glycogen storage diseases (types 1 and 3). Note=The disease is caused by mutations affecting the gene represented in this entry. Bi-allelic inactivation of HNF1A, whether sporadic or associated with MODY3, may be an early step in the development of some hepatocellular carcinomas.; DISEASE: Maturity-onset diabetes of the young 3 (MODY3) [MIM:600496]: 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:10078571, ECO:0000269|PubMed:10102714, ECO:0000269|PubMed:10482964, ECO:0000269|PubMed:10588527, ECO:0000269|PubMed:10966642, ECO:0000269|PubMed:12453420, ECO:0000269|PubMed:17573900, ECO:0000269|PubMed:8945470, ECO:0000269|PubMed:9032114, ECO:0000269|PubMed:9075818, ECO:0000269|PubMed:9075819, ECO:0000269|PubMed:9097962, ECO:0000269|PubMed:9166684, ECO:0000269|PubMed:9287053, ECO:0000269|PubMed:9392505, ECO:0000269|PubMed:9626139, ECO:0000269|PubMed:9754819}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent, 20 (IDDM20) [MIM:612520]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:10333057, ECO:0000269|PubMed:9313763, ECO:0000269|PubMed:9867222}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0579
- RVIS EVS
- -0.44
- RVIS percentile EVS
- 24.6
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.991
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |