FOXH1

forkhead box H1, the group of Forkhead boxes

Basic information

Region (hg38): 8:144473411-144475849

Links

ENSG00000160973 ∙ NCBI:8928 ∙ OMIM:603621 ∙ HGNC:3814 ∙ Uniprot:O75593 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital heart malformation (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital heart malformations	AD	Cardiovascular	The condition may involve congenital heart anomalies, which may benefit from early identification and management	Cardiovascular; Craniofacial; Endocrine; Neurologic	18538293
Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FOXH1 gene.

• Holoprosencephaly sequence (130 variants)
• not provided (43 variants)
• Inborn genetic diseases (26 variants)
• not specified (14 variants)
• Conotruncal defect (7 variants)
• FOXH1-related condition (6 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FOXH1 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			3	29	7	39
missense		6	96	7	1	110
nonsense			3			3
start loss						0
frameshift						0
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding			13	4	7	24
Total	0	6	117	40	15

Highest pathogenic variant AF is 0.00000657

Variants in FOXH1

This is a list of pathogenic ClinVar variants found in the FOXH1 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-144473424-C-T		not specified	Likely benign (Aug 20, 2023)
8-144473425-C-T		not specified	Uncertain significance (Dec 08, 2023)
8-144473766-C-A		Holoprosencephaly sequence	Benign (Jan 13, 2018)
8-144473787-G-A		Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
8-144473802-C-T		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144473808-C-T		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144473815-C-T		Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
8-144473856-G-A		Holoprosencephaly sequence	Uncertain significance (Apr 06, 2018)
8-144473884-G-A		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144473916-G-T		Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
8-144473927-G-A		Holoprosencephaly sequence	Benign (Jan 13, 2018)
8-144473998-GCTC-G		Holoprosencephaly sequence	Uncertain significance (Jun 14, 2016)
8-144474005-C-T		Holoprosencephaly sequence	Likely benign (Jan 13, 2018)
8-144474066-G-C		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144474150-T-C		Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
8-144474164-C-T		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144474183-G-A		Holoprosencephaly sequence	Benign (Jan 13, 2018)
8-144474215-G-A		Holoprosencephaly sequence	Likely benign (Jan 12, 2018)
8-144474217-G-T		Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
8-144474218-T-C		not specified • Holoprosencephaly sequence	Benign (Jul 29, 2023)
8-144474259-C-T		not specified • Holoprosencephaly sequence	Benign (Jan 23, 2024)
8-144474265-G-A		Holoprosencephaly sequence	Likely benign (Nov 04, 2022)
8-144474276-G-A		Holoprosencephaly sequence	Uncertain significance (Dec 21, 2021)
8-144474279-C-T		Holoprosencephaly sequence	Uncertain significance (Sep 08, 2023)
8-144474280-C-T		Holoprosencephaly sequence	Uncertain significance (Feb 11, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FOXH1	protein_coding	protein_coding	ENST00000377317	3	2924

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0416	0.932	125497	0	17	125514	0.0000677

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-2.55	278	182	1.53	0.00000877	2255
Missense in Polyphen		74	63.612	1.1633		858
Synonymous	-2.59	110	80.5	1.37	0.00000408	810
Loss of Function	1.93	4	10.9	0.368	4.76e-7	127

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000868	0.0000868
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000863	0.0000794
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000982	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional activator. Recognizes and binds to the DNA sequence 5'-TGT[GT][GT]ATT-3'. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling. Forms a transcriptionally active complex containing FOXH1/SMAD2/SMAD4 on a site on the GSC promoter called TARE (TGF-beta/activin response element). {ECO:0000269|PubMed:9702198}.
• Pathway: TGF-Ncore;Heart Development;Endoderm Differentiation;Mesodermal Commitment Pathway;TGF-beta Signaling Pathway;TGF-beta Receptor Signaling;Developmental Biology;Signal Transduction;Signaling by Activin;Signaling by NODAL;TGF_beta_Receptor;Signaling by TGF-beta family members;Regulation of nuclear SMAD2/3 signaling (Consensus)

Recessive Scores

• pRec: 0.242

Intolerance Scores

• loftool: 0.137
• rvis_EVS: 0
• rvis_percentile_EVS: 53.85

Haploinsufficiency Scores

• pHI: 0.716
• hipred: Y
• hipred_score: 0.553
• ghis: 0.406

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.904

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Foxh1
• Phenotype: respiratory system phenotype; embryo phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); vision/eye phenotype; digestive/alimentary phenotype; hearing/vestibular/ear 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); renal/urinary system phenotype; skeleton phenotype; immune system phenotype; homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; craniofacial phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: foxh1
• Affected structure: secondary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;heart looping;secondary heart field specification;outflow tract morphogenesis;cardiac right ventricle morphogenesis;ventricular trabecula myocardium morphogenesis;transforming growth factor beta receptor signaling pathway;negative regulation of intracellular estrogen receptor signaling pathway;embryonic heart tube anterior/posterior pattern specification;aorta morphogenesis;negative regulation of DNA-binding transcription factor activity;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;axial mesoderm development;negative regulation of androgen receptor signaling pathway;cellular response to cytokine stimulus;nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;activin responsive factor 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;protein domain specific binding;enhancer binding;bHLH transcription factor binding;sequence-specific DNA binding;transcription regulatory region DNA binding;SMAD binding;androgen receptor binding;co-SMAD binding;R-SMAD binding