GeneBe

HNF4A

protein-coding

hepatocyte nuclear factor 4 alpha, the group of Hepatocyte nuclear factor 4 family|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]

Previous symbols:
  • TCF14
  • MODY
  • MODY1

MANE transcript

NM_175914.5

Inheritance

AD

ClinVar variants

P:169U:226B:111

Top phenotype

Congenital hyperinsulinism, diazoxide-responsive; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young; Maturity onset diabetes of the young, 1

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr20:44,355,699-44,432,845

External References & Databases

Ensembl (ENSG00000101076)NCBI Gene (3172)OMIM (600281)HGNC:5024GenCCUniProt (P41235)AlphaFoldClinVar (HNF4A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~77.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

maturity-onset diabetes of the young type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007452

Submitter: Ambry Genetics

maturity-onset diabetes of the young type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007452

Submitter: PanelApp Australia

maturity-onset diabetes of the youngSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018911

Submitter: Orphanet

monogenic diabetesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: ClinGen

HNF4A was first reported in relation to autosomal dominant monogenic diabetes (more specifically in maturity onset diabetes of the young/ MODY) in 1996 (Yamagata et al., 1996 PMID: 8945471). HNF4A is a transcription factor expressed within the liver, kidney, and pancreas of humans (Drewes et al., 1996 PMID: 8622695). HNF4A has been shown to regulate the expression of HNF1A, another transcription factor that is associated with monogenic diabetes, providing a direct correlation between these monogenic diabetes associated genes (Thomas et al., 2001 PMID: 11590126). Numerous variants in HNF4A in relation to the development of monogenic diabetes ( or MODY and hyperinsulinemic hypoglycemia), including missense, frameshift, nonsense and deletions have been reported in humans. There are databases describing HNF4A variants of interest in monogenic diabetes, including: (1) the HNF4A database in LOVD (https://grenada.lumc.nl/LOVD2/diabetes/home.php?select_db=HNF4A); and (2) The Diagnostic Mutation Database (https://secure.dmudb.net/ngrl-rep/Home.do) (Colclough et al., 2013 PMID: 23348805). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level and segregation data is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies, biochemical evidence, and animal models. HNF4A has been associated with multiple disease entities and/or phenotypes through autosomal dominant germline inheritance, including: (1) Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young (MIM: 616026); (2) MODY, type I (MIM: 125850); (3) Susceptibility to Diabetes mellitus, noninsulin-dependent (MIM: 125853). The Fanconi renotubular syndrome 4 (FRST4) is associated with a single variant in HNF4A, p.Arg76Trp (aka p.Arg85Trp or Arg63Trp dependent on the transcript used, ref. Flanagan et al., 2010 PMID: 20164212, supplementary table 1) and has been shown to occur in at least 7 different probands (PMIDs: 22802087, 24285859, 25819479, 30005691, 28693455, 28458902, 27245055, 20164212). Renal abnormalities often accompany a diagnosis of MODY. Per the criteria outline by the ClinGen Lumping and Splitting Working Group, FRST4 and MODY1 show the same molecular mechanism and phenotypes consistent with a spectrum of MODY diagnosis, therefore they have been lumped into the disease entity, monogenic diabetes (MONDO:0015967). The susceptibility to diabetes mellitus, non-insulin dependent is not currently curated under this gene-disease relationship and will be evaluated independently. In summary, HNF4A is DEFINITIVELY associated with autosomal dominant monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes Expert Panel on Feb 26, 2019.

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the youngSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014458

Submitter: PanelApp Australia

maturity-onset diabetes of the young type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007452

Submitter: Labcorp Genetics (formerly Invitae)

maturity-onset diabetes of the young type 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007452

Submitter: G2P

diabetes mellitus, noninsulin-dependentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the youngSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014458

Submitter: G2P

hyperinsulinism due to HNF4A deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016988

Submitter: Orphanet

maturity-onset diabetes of the young type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007452

Submitter: Genomics England PanelApp

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the youngSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014458

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Congenital hyperinsulinism, diazoxide-responsive; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young; Maturity onset diabetes of the young, 1AD

Manifestation: Endocrine; Renal

Intervention: Endocrine; Renal

Rationale: Individuals can present in childhood with macrosomia and hyperinsulinism, which has been reported as diazoxide-responsive; For individuals whose phenotype includes Fanconi syndrome, awareness may allow prompt treatment through replacement of lost solutes

Refs: 8945471; 9313765; 9294105; 9449683; 9920109; 11232004; 12050210; 17407387; 21683639; 21922456; 22802087; 24285859Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNF4A variants in ClinVar

16 Conditions Cataloged
not providedTotal: 345
Monogenic diabetesTotal: 213
Maturity-onset diabetes of the young type 1Total: 196
Maturity-onset diabetes of the youngTotal: 170
not specifiedTotal: 129
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the youngTotal: 101
Type 2 diabetes mellitusTotal: 99
HNF4A-related disorderTotal: 67

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_175914.5. 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.

EffectPLPVUSLBBSum
synonymous
5
clinvar
89
clinvar
5
clinvar
 99
missense
21
clinvar
55
clinvar
217
clinvar
10
clinvar
7
clinvar
 310
nonsense
23
clinvar
9
clinvar
2
clinvar
 34
start loss
1
clinvar
5
clinvar
 6
frameshift
16
clinvar
15
clinvar
 31
splice donor/acceptor (+/-2bp)
6
clinvar
18
clinvar
2
clinvar
 26
Total671022269912506

Highest pathogenic variant AF is 0.000115269206

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_175914.5RefSeqNP_787110.210MANE Select
ENST00000316673.9EnsemblENSP00000315180.410MANE Select
NM_000457.6RefSeqNP_000448.310Standard
NM_001030003.3RefSeqNP_001025174.110Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
hnf4aDanio 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)
  • AMPK signaling pathway - Homo sapiens (human)
  • Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
  • NHR
  • AMP-activated Protein Kinase (AMPK) Signaling

Biological Process

  • type B pancreatic cell development
  • regulation of transcription by RNA polymerase II
  • transcription initiation from RNA polymerase II promoter
  • ornithine metabolic process
  • lipid metabolic process

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • RNA polymerase II activating transcription factor binding
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA binding

Cellular Component

  • nucleus
  • nucleoplasm
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000316099
Coding exons
10
Length
77146
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125748
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.812062930.7030.00002033091
Missense (PolyPhen)74139.670.529811482
Synonymous-0.7851401291.090.00000983950
Loss of Function3.34623.40.2560.00000136249

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.000110.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000350.000035rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1- antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1- alpha. May be essential for development of the liver, kidney and intestine.;
Disease
DISEASE: Maturity-onset diabetes of the young 1 (MODY1) [MIM:125850]: 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:10389854, ECO:0000269|PubMed:17407387, ECO:0000269|PubMed:9243109, ECO:0000269|PubMed:9313765}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:9449683}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (FRTS4) [MIM:616026]: A disease characterized by Fanconi syndrome associated with a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Fanconi syndrome is a proximal tubulopathy resulting in generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricemia. Some FRTS4 patients have nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcemia, and hypermagnesemia. {ECO:0000269|PubMed:22802087, ECO:0000269|PubMed:24285859}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.938

Intolerance Scores

LoFtool
0.0136
RVIS EVS
-0.96
RVIS percentile EVS
9.17

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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