HNF1A

HNF1 homeobox A, the group of HNF class homeoboxes

Basic information

Region (hg38): 12:120978543-121002512

Previous symbols: [ "MODY3", "TCF1" ]

Links

ENSG00000135100

∙ NCBI:6927 ∙ OMIM:142410 ∙ HGNC:11621 ∙ Uniprot:P20823 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

nonpapillary renal cell carcinoma (No Known Disease Relationship), mode of inheritance: Unknown
type 1 diabetes mellitus 20 (Strong), mode of inheritance: AD
diabetes mellitus, noninsulin-dependent (Strong), mode of inheritance: AD
maturity-onset diabetes of the young type 3 (Strong), mode of inheritance: AD
type 1 diabetes mellitus 20 (Definitive), mode of inheritance: AD
maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
hyperinsulinism due to HNF1A deficiency (Supportive), mode of inheritance: AD
maturity-onset diabetes of the young type 3 (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
Renal cell carcinoma, nonpapillary clear cell; Liver adenomatosis; Maturity onset diabetes of the young, type 3	AD	Endocrine; Oncologic	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	Endocrine; Oncologic	8945470; 9313763; 10482964; 11058894; 10649494; 11575290; 11668618; 11904371; 12050210; 12355088; 12355088; 14598263; 15001650; 15649945; 21120312; 21683639; 22517943; 22802087

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HNF1A gene.

not_provided (591 variants)
Monogenic_diabetes (404 variants)
Maturity_onset_diabetes_mellitus_in_young (332 variants)
Maturity-onset_diabetes_of_the_young_type_3 (292 variants)
Type_1_diabetes_mellitus_20 (157 variants)
not_specified (157 variants)
Diabetes_mellitus_type_1 (147 variants)
Nonpapillary_renal_cell_carcinoma (146 variants)
Type_2_diabetes_mellitus (146 variants)
Hepatic_adenomas,_familial (142 variants)
HNF1A-related_disorder (63 variants)
Diabetes_mellitus (9 variants)
Ovarian_cancer (2 variants)
Clear_cell_carcinoma_of_kidney (2 variants)
DiGeorge_syndrome (1 variants)
Hyperinsulinism_due_to_HNF1A_deficiency (1 variants)
Keratoderma-ichthyosis-deafness_syndrome,_autosomal_recessive (1 variants)
Diabetes_mellitus_type_2,_susceptibility_to (1 variants)
Maturity-onset_diabetes_of_the_young_type_1 (1 variants)
Chromophobe_renal_cell_carcinoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HNF1A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000545.8. Only rare variants are included in the table.

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.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	3 clinvar	8 clinvar	158 clinvar	7 clinvar	178
missense	50 clinvar	95 clinvar	323 clinvar	27 clinvar	16 clinvar	511
nonsense	40 clinvar	18 clinvar	2 clinvar			60
start loss	3	2				5
frameshift	71 clinvar	54 clinvar	7 clinvar			132
splice donor/acceptor (+/-2bp)	19 clinvar	23 clinvar	2 clinvar			44
Total	185	195	342	185	23

Highest pathogenic variant AF is 0.00009528586

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HNF1A	protein_coding	protein_coding	ENST00000257555	10	23970

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.961	0.0389	125710	0	8	125718	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.14	318	380	0.836	0.0000240	4043
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000580	0.0000580
Ashkenazi Jewish	0.000101	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000466	0.0000440
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.;
Pathway: 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;Vitamin D Receptor Pathway;Hepatitis C and Hepatocellular Carcinoma;Development and heterogeneity of the ILC family;ESC Pluripotency Pathways;Role of Osx and miRNAs in tooth development;wnt signaling pathway;growth hormone signaling pathway;role of mal in rho-mediated activation of srf;FOXA2 and FOXA3 transcription factor networks;Presenilin action in Notch and Wnt signaling (Consensus)

Intolerance Scores

loftool: 0.0579
rvis_EVS: -0.44
rvis_percentile_EVS: 24.6

Haploinsufficiency Scores

pHI: 0.866
hipred: Y
hipred_score: 0.835
ghis: 0.458

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.991

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

Gene name: Hnf1a
Phenotype: adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); reproductive system phenotype; digestive/alimentary phenotype; renal/urinary system phenotype; skeleton phenotype;

Zebrafish Information Network

Gene name: hnf1a
Affected structure: pancreatic B cell
Phenotype tag: abnormal
Phenotype quality: decreased area

Gene ontology

Biological process: natural killer cell differentiation;liver development;regulation of transcription by RNA polymerase II;insulin secretion;pancreas development;regulation of pronephros size;renal glucose absorption;glucose homeostasis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;glucose import;positive regulation of transcription initiation from RNA polymerase II promoter
Cellular component: nucleus;cytoplasm;protein-containing complex
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;transcription regulatory region DNA binding;protein dimerization activity