FOXA1

protein-coding

forkhead box A1, the group of Forkhead boxes

Gene summary

This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific transcripts such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. [provided by RefSeq, Jul 2008]

Previous symbols:

HNF3A

MANE transcript

NM_004496.5

Inheritance

—

ClinVar variants

U:77B:5

Top phenotype

Paroxysmal choreoathetosis

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr14:37,589,552-37,596,059

External References & Databases

Ensembl (ENSG00000129514)

Transcript & Mutation Effects

hg38 • Region Span ~6.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXA1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 76

not providedTotal: 3

Paroxysmal choreoathetosisTotal: 1

ScoliosisTotal: 1

Imperforate anusTotal: 1

BronchiectasisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004496.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				1 clinvar	2 clinvar	3
missense			76 clinvar	2 clinvar		78
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	77	3	2	82

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004496.5	RefSeq	NP_004487.2	2	MANE Select
ENST00000250448.5	Ensembl	ENSP00000250448.3	2	MANE Select
ENST00000553751.1	Ensembl	ENSP00000451704.1	2	Standard
ENST00000995306.1	Ensembl	ENSP00000665123.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxa1	Danio rerio	Structure: goblet cell Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

foxa1

Danio rerio

Structure: goblet cell

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Androgen Receptor Network in Prostate Cancer
Endoderm Differentiation
Mesodermal Commitment Pathway
Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
Signal Transduction

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin remodeling
regulation of transcription by RNA polymerase II
Notch signaling pathway
anatomical structure morphogenesis

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

fibrillar center
nucleus
nucleoplasm
microvillus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000250448
Coding exons: 2
Length: 10057
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125731
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.439	243	263	0.924	0.0000122	3040
Missense (PolyPhen)		59	86.317	0.68353		1020
Synonymous	-1.01	130	116	1.12	0.00000584	974
Loss of Function	2.31	3	11.5	0.262	4.92e-7	134

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00012	0.000092	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Its differential recruitment to chromatin is dependent on distribution of histone H3 methylated at 'Lys-5' (H3K4me2) in estrogen-regulated genes. Involved in the development of multiple endoderm-derived organ systems such as liver, pancreas, lung and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles (By similarity). Modulates the transcriptional activity of nuclear hormone receptors. Is involved in ESR1-mediated transcription; required for ESR1 binding to the NKX2-1 promoter in breast cancer cells; binds to the RPRM promoter and is required for the estrogen-induced repression of RPRM. Involved in regulation of apoptosis by inhibiting the expression of BCL2. Involved in cell cycle regulation by activating expression of CDKN1B, alone or in conjunction with BRCA1. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis. {ECO:0000250, ECO:0000269|PubMed:16087863, ECO:0000269|PubMed:16331276, ECO:0000269|PubMed:18358809, ECO:0000269|PubMed:19127412, ECO:0000269|PubMed:19917725}.;

Recessive Scores

pRec: 0.432

Intolerance Scores

LoFtool: 0.0959
RVIS EVS: 0.62
RVIS percentile EVS: 83.14

Essentials

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

Gene Damage Prediction

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