HNF4A

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

Basic information

Region (hg38): 20:44355698-44432845

Previous symbols: [ "TCF14", "MODY", "MODY1" ]

Links

ENSG00000101076 ∙ NCBI:3172 ∙ OMIM:600281 ∙ HGNC:5024 ∙ Uniprot:P41235 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• maturity-onset diabetes of the young type 1 (Definitive), mode of inheritance: AD
• diabetes mellitus, noninsulin-dependent (Strong), mode of inheritance: AD
• maturity-onset diabetes of the young type 1 (Strong), mode of inheritance: AD
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (Strong), mode of inheritance: AD
• maturity-onset diabetes of the young type 1 (Definitive), mode of inheritance: AD
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (Definitive), mode of inheritance: AD
• maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
• hyperinsulinism due to HNF4A deficiency (Supportive), mode of inheritance: AD
• maturity-onset diabetes of the young type 1 (Strong), mode of inheritance: AD
• monogenic diabetes (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital hyperinsulinism, diazoxide-responsive; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young; Maturity onset diabetes of the young, 1	AD	Endocrine; Renal	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	Endocrine; Renal	8945471; 9313765; 9294105; 9449683; 9920109; 11232004; 12050210; 17407387; 21683639; 21922456; 22802087; 24285859

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HNF4A gene.

• Maturity onset diabetes mellitus in young (270 variants)
• not provided (266 variants)
• Maturity-onset diabetes of the young type 1 (175 variants)
• Familial hyperinsulinism (114 variants)
• not specified (74 variants)
• Monogenic diabetes (64 variants)
• Hyperinsulinism, Dominant (21 variants)
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Type 2 diabetes mellitus;Maturity-onset diabetes of the young type 1 (13 variants)
• Maturity-onset diabetes of the young type 1;Type 2 diabetes mellitus;Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (9 variants)
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (8 variants)
• Maturity-onset diabetes of the young type 1;Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Type 2 diabetes mellitus (8 variants)
• HNF4A-related condition (7 variants)
• Type 2 diabetes mellitus;Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Maturity-onset diabetes of the young type 1 (7 variants)
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Maturity-onset diabetes of the young type 1;Type 2 diabetes mellitus (6 variants)
• Type 2 diabetes mellitus (6 variants)
• Hyperinsulinemia (2 variants)
• Inborn genetic diseases (2 variants)
• Maturity-onset diabetes of the young type 1;Type 2 diabetes mellitus (2 variants)
• Hyperinsulinism due to HNF4A deficiency (2 variants)
• Glycosuria (1 variants)
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Maturity-onset diabetes of the young type 1 (1 variants)
• Maturity-onset diabetes of the young type 3 (1 variants)
• Hyperinsulinism due to HNF1A deficiency (1 variants)
• Autosomal dominant polycystic liver disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HNF4A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	36	2	40
missense	8	16	97	4	2	127
nonsense	16	2	2			20
start loss		2	1			3
frameshift	3	5				8
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)	4	11				15
splice region		2	4	8		14
non coding	1		27	55	41	124
Total	32	37	131	95	45

Highest pathogenic variant AF is 0.0000658

Variants in HNF4A

This is a list of pathogenic ClinVar variants found in the HNF4A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
20-44355722-C-T		not specified • Maturity onset diabetes mellitus in young	Uncertain significance/Uncertain risk allele (Nov 23, 2016)
20-44355726-C-T		Maturity-onset diabetes of the young type 1;Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Type 2 diabetes mellitus	Uncertain significance (May 21, 2023)
20-44355759-C-A		not specified	Uncertain significance (Mar 24, 2020)
20-44355761-C-T		not specified	Uncertain significance (Oct 02, 2018)
20-44355787-G-A		not specified	Uncertain significance (Dec 26, 2019)
20-44355804-CA-C		Maturity-onset diabetes of the young type 1 • Monogenic diabetes	Likely pathogenic (Apr 06, 2024)
20-44355806-T-C		Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young • Maturity onset diabetes mellitus in young • Monogenic diabetes	Likely pathogenic (Jan 02, 2024)
20-44355807-G-A		Maturity-onset diabetes of the young type 1 • Monogenic diabetes	Likely pathogenic (Apr 06, 2024)
20-44355811-A-C		Maturity onset diabetes mellitus in young • Maturity-onset diabetes of the young type 1;Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young;Type 2 diabetes mellitus	Conflicting classifications of pathogenicity (Feb 27, 2023)
20-44355816-G-C			Likely benign (Jun 15, 2023)
20-44355850-T-TA		Hyperinsulinism due to HNF1A deficiency	Pathogenic (Dec 13, 2019)
20-44355852-C-A		Maturity-onset diabetes of the young type 1	Pathogenic (Oct 05, 2021)
20-44355852-C-G		Maturity-onset diabetes of the young type 1 • Monogenic diabetes	Pathogenic (Jan 22, 2024)
20-44355854-G-T		Maturity-onset diabetes of the young type 1	Likely pathogenic (-)
20-44355866-G-A		not specified • Maturity onset diabetes mellitus in young	Conflicting classifications of pathogenicity (Nov 10, 2020)
20-44355868-G-A			Likely benign (Jun 20, 2022)
20-44401024-T-C			Benign (Jul 14, 2018)
20-44401262-AAAGG-A		Maturity onset diabetes mellitus in young • Hyperinsulinism, Dominant	Conflicting classifications of pathogenicity (Jun 14, 2016)
20-44401297-GGGAGGGC-G		HNF4A-related disorder • not specified	Benign/Likely benign (Jan 04, 2024)
20-44401300-A-G		HNF4A-related disorder	Likely benign (Mar 10, 2020)
20-44401304-C-G		HNF4A-related disorder	Likely benign (Mar 10, 2020)
20-44401305-G-A		Maturity-onset diabetes of the young type 1 • Familial hyperinsulinism • Maturity onset diabetes mellitus in young • HNF4A-related disorder	Conflicting classifications of pathogenicity (Oct 29, 2023)
20-44401307-A-G			Likely benign (Dec 28, 2021)
20-44401311-C-G		HNF4A-related disorder	Likely benign (Mar 29, 2019)
20-44401312-G-A		HNF4A-related disorder	Benign/Likely benign (Jan 22, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HNF4A	protein_coding	protein_coding	ENST00000316099	10	77146

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.153	0.847	125737	0	11	125748	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.81	206	293	0.703	0.0000203	3091
Missense in Polyphen		74	139.67	0.52981		1482
Synonymous	-0.785	140	129	1.09	0.00000983	950
Loss of Function	3.34	6	23.4	0.256	0.00000136	249

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.000300	0.000298
East Asian	0.000109	0.000109
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.000109	0.000109
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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;Nuclear Receptors;Mesodermal Commitment Pathway;Gene expression (Transcription);Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;TGF_beta_Receptor;HIF-1-alpha transcription factor network;FOXA2 and FOXA3 transcription factor networks;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.938

Intolerance Scores

• loftool: 0.0136
• rvis_EVS: -0.96
• rvis_percentile_EVS: 9.17

Haploinsufficiency Scores

• pHI: 0.945
• hipred: Y
• hipred_score: 0.819
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hnf4a
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); embryo phenotype; liver/biliary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: hnf4a
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: decreased area

Gene ontology

• 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;xenobiotic metabolic process;sex differentiation;blood coagulation;negative regulation of cell population proliferation;response to glucose;regulation of gastrulation;regulation of lipid metabolic process;signal transduction involved in regulation of gene expression;negative regulation of cell growth;intracellular receptor signaling pathway;glucose homeostasis;cholesterol homeostasis;steroid hormone mediated signaling pathway;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;regulation of insulin secretion;lipid homeostasis;phospholipid homeostasis;SMAD protein signal transduction;triglyceride homeostasis;hepatocyte differentiation
• Cellular component: nucleus;nucleoplasm;cytoplasm
• 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;DNA-binding transcription factor activity;steroid hormone receptor activity;nuclear receptor activity;signaling receptor binding;fatty acid binding;protein binding;zinc ion binding;protein homodimerization activity;transcription regulatory region DNA binding