HNF1A

protein-coding

HNF1 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]

Previous symbols:
  • MODY3
  • TCF1

MANE transcript

NM_000545.8

Inheritance

AD

ClinVar variants

P:408U:372B:235

Top phenotype

Renal cell carcinoma, nonpapillary clear cell; Liver adenomatosis; Maturity onset diabetes of the young, type 3

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr12:120,978,543-121,002,512

External References & Databases

Transcript & Mutation Effects

hg38 • Region Span ~24.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

maturity-onset diabetes of the young type 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010894

Submitter: Genomics England PanelApp

type 1 diabetes mellitus 20STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012919

Submitter: Genomics England PanelApp

diabetes mellitus, noninsulin-dependentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

monogenic diabetesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: PanelApp Australia

type 1 diabetes mellitus 20DEFINITIVE

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.

monogenic diabetesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: ClinGen

nonpapillary renal cell carcinomaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007763

Submitter: Labcorp Genetics (formerly Invitae)

maturity-onset diabetes of the young type 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010894

Submitter: PanelApp Australia

maturity-onset diabetes of the young type 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010894

Submitter: Labcorp Genetics (formerly Invitae)

maturity-onset diabetes of the youngSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

hyperinsulinism due to HNF1A deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017935

Submitter: Orphanet

Clinical Genomic Database (CGD)

Renal cell carcinoma, nonpapillary clear cell; Liver adenomatosis; Maturity onset diabetes of the young, type 3AD

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

Refs: 8945470; 9313763; 10482964; 11058894; 10649494; 11575290; 11668618; 11904371; 12050210; 12355088; 12355088; 14598263; 15001650; 15649945; 21120312; 21683639; 22517943; 22802087Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNF1A variants in ClinVar

24 Conditions Cataloged
not providedTotal: 677
Monogenic diabetesTotal: 426
Maturity-onset diabetes of the youngTotal: 339
Maturity-onset diabetes of the young type 3Total: 308
not specifiedTotal: 169
Type 1 diabetes mellitus 20Total: 157
Diabetes mellitus type 1Total: 147
Nonpapillary renal cell carcinomaTotal: 146

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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
7
clinvar
178
clinvar
7
clinvar
197
missense
53
clinvar
104
clinvar
354
clinvar
30
clinvar
19
clinvar
560
nonsense
41
clinvar
19
clinvar
1
clinvar
1
clinvar
62
start loss
3
clinvar
2
clinvar
5
frameshift
79
clinvar
59
clinvar
7
clinvar
145
splice donor/acceptor (+/-2bp)
21
clinvar
22
clinvar
3
clinvar
46
Total199209372209261015

Highest pathogenic variant AF is 0.00009528586

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000545.8RefSeqNP_000536.610MANE Select
ENST00000257555.11EnsemblENSP00000257555.510MANE Select
NM_001306179.2RefSeqNP_001293108.210Standard
NM_001406915.1RefSeqNP_001393844.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hnf1aDanio 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: gnomAD

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-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.143183800.8360.00002404043
Missense (PolyPhen)80114.450.698981266
Synonymous-1.422011771.140.00001241361
Loss of Function4.18427.80.1440.00000154278

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000470.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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