FGF8

fibroblast growth factor 8, the group of Receptor ligands|Fibroblast growth factor family

Basic information

Region (hg38): 10:101770108-101780371

Links

ENSG00000107831 ∙ NCBI:2253 ∙ OMIM:600483 ∙ HGNC:3686 ∙ Uniprot:P55075 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hypogonadotropic hypogonadism 6 with or without anosmia (Strong), mode of inheritance: AD
• holoprosencephaly (Supportive), mode of inheritance: AR
• Kallmann syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 6 with or without anosmia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 6, with or without anosmia	AD/Digenic	Endocrine	In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Craniofacial; Dental; Endocrine; Musculoskeletal; Neurologic	18596921; 21045958; 21832120; 20301509; 21976454; 22319038
Relatively complex patterns of inheritance (eg, involving variants in FGFR1) have been described; Hypoplastic femurs and pelvis is caused by a genomic rearrangement that causes a regulatory position effect on FGF8

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FGF8 gene.

• not provided (52 variants)
• Holoprosencephaly sequence (12 variants)
• Hypogonadotropic hypogonadism 6 with or without anosmia (12 variants)
• not specified (6 variants)
• Inborn genetic diseases (3 variants)
• Holoprosencephaly 1 (2 variants)
• Peters plus syndrome (1 variants)
• FGF8-related condition (1 variants)
• Semilobar holoprosencephaly (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FGF8 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			1	9	1	11
missense		5	24	2		31
nonsense	2					2
start loss						0
frameshift		2				2
inframe indel	1					1
splice donor/acceptor (+/-2bp)		2	1			3
splice region			2	2		4
non coding				5	6	11
Total	3	9	26	16	7

Variants in FGF8

This is a list of pathogenic ClinVar variants found in the FGF8 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-101770141-TA-T			Benign (Aug 13, 2019)
10-101770141-TAAAAAAAAAAAA-T			Benign (Sep 14, 2019)
10-101770141-T-TA			Benign (Aug 21, 2019)
10-101770205-C-G			Likely benign (Jul 14, 2018)
10-101770353-C-T			Likely benign (Nov 17, 2023)
10-101770366-C-T			Uncertain significance (Oct 22, 2023)
10-101770367-G-A		Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
10-101770378-G-A		Hypogonadotropic hypogonadism 6 with or without anosmia • Holoprosencephaly 1	Conflicting classifications of pathogenicity (Nov 19, 2023)
10-101770403-C-T		Inborn genetic diseases	Uncertain significance (Aug 31, 2022)
10-101770409-G-A			Uncertain significance (Jul 01, 2022)
10-101770422-G-A		not specified • FGF8-related disorder	Benign/Likely benign (Nov 10, 2023)
10-101770434-G-GCC		Hypogonadotropic hypogonadism 6 with or without anosmia	Likely pathogenic (Jun 16, 2016)
10-101770447-C-T		Holoprosencephaly sequence • See cases	Likely pathogenic (Dec 08, 2021)
10-101770482-C-T		not specified	Benign/Likely benign (Jun 01, 2023)
10-101770490-AGCCCTTGCGGGGCCG-A		Holoprosencephaly sequence	Pathogenic (Jul 27, 2021)
10-101770505-G-A			Uncertain significance (Jun 21, 2019)
10-101770514-G-A		FGF8-related disorder	Uncertain significance (Dec 22, 2022)
10-101770538-C-T		Microcephaly	Uncertain significance (-)
10-101770541-A-G			Uncertain significance (Dec 21, 2022)
10-101770556-G-A			Uncertain significance (Jul 09, 2019)
10-101770557-C-T			Likely benign (May 02, 2018)
10-101770558-G-A		Holoprosencephaly 1	Likely benign (May 28, 2019)
10-101770562-T-A		Inborn genetic diseases	Uncertain significance (Dec 09, 2023)
10-101770567-T-C		Holoprosencephaly sequence	Uncertain significance (Apr 18, 2018)
10-101770595-C-A		Holoprosencephaly sequence	Likely pathogenic (Apr 18, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FGF8	protein_coding	protein_coding	ENST00000320185	6	5956

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.677	0.322	125739	0	1	125740	0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.57	99	154	0.644	0.0000102	1546
Missense in Polyphen		25	42.262	0.59155		381
Synonymous	0.0687	66	66.7	0.989	0.00000433	500
Loss of Function	2.73	2	12.4	0.162	6.83e-7	128

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays an important role in the regulation of embryonic development, cell proliferation, cell differentiation and cell migration. Required for normal brain, eye, ear and limb development during embryogenesis. Required for normal development of the gonadotropin-releasing hormone (GnRH) neuronal system (PubMed:16384934, PubMed:16597617, PubMed:8663044). Plays a role in neurite outgrowth in hippocampal cells (PubMed:21576111). {ECO:0000269|PubMed:16384934, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:21576111, ECO:0000269|PubMed:8663044}.
• Disease: DISEASE: Hypogonadotropic hypogonadism 6 with or without anosmia (HH6) [MIM:612702]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:18596921, ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in FGF8 as well as in other HH- associated genes including FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Melanoma - Homo sapiens (human);Breast cancer - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Heart Development;Neural Crest Differentiation;Differentiation Pathway;Gene regulatory network modelling somitogenesis;Dopaminergic Neurogenesis;Mesodermal Commitment Pathway;Tgif disruption of Shh signaling;MAPK Signaling Pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Regulation of Actin Cytoskeleton;FGFR2c ligand binding and activation;FGFR2 ligand binding and activation;FRS-mediated FGFR2 signaling;Negative regulation of FGFR2 signaling;Signaling by FGFR2;FGFR3b ligand binding and activation;Phospholipase C-mediated cascade; FGFR2;FGFR3c ligand binding and activation;SHC-mediated cascade:FGFR2;FRS-mediated FGFR3 signaling;PI-3K cascade:FGFR2;Downstream signaling of activated FGFR2;SHC-mediated cascade:FGFR3;PI-3K cascade:FGFR4;PI-3K cascade:FGFR3;Downstream signaling of activated FGFR3;Disease;Negative regulation of FGFR3 signaling;Signaling by FGFR3;FGFR4 ligand binding and activation;Signal Transduction;FRS-mediated FGFR4 signaling;SHC-mediated cascade:FGFR4;Downstream signaling of activated FGFR4;Negative regulation of FGFR4 signaling;Signaling by FGFR4;Signaling by FGFR;FGFR3 ligand binding and activation;FGFR3 mutant receptor activation;PI3K Cascade;IRS-mediated signalling;Insulin receptor signalling cascade;Activated point mutants of FGFR2;Signaling by Insulin receptor;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;FGF;Signaling by FGFR2 in disease;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Signaling by activated point mutants of FGFR3;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;FGFR2 mutant receptor activation;Signaling by FGFR3 point mutants in cancer;Signaling by FGFR3 in disease;Signaling by FGFR in disease;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;GPCR signaling-G alpha i;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by activated point mutants of FGFR1;FGFR1 mutant receptor activation;Signaling by FGFR1 in disease;Signaling by Receptor Tyrosine Kinases;Intracellular signaling by second messengers;Phospholipase C-mediated cascade: FGFR1;Diseases of signal transduction;Downstream signaling of activated FGFR1;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);FGFR1c ligand binding and activation;FGFR1 ligand binding and activation;FGFRL1 modulation of FGFR1 signaling;FRS-mediated FGFR1 signaling;SHC-mediated cascade:FGFR1;PI-3K cascade:FGFR1;Negative regulation of FGFR1 signaling;Signaling by FGFR1;Phospholipase C-mediated cascade; FGFR3;Phospholipase C-mediated cascade; FGFR4 (Consensus)

Recessive Scores

• pRec: 0.586

Intolerance Scores

• rvis_EVS: -0.32
• rvis_percentile_EVS: 31.46

Haploinsufficiency Scores

• pHI: 0.536
• hipred: Y
• hipred_score: 0.798
• ghis: 0.531

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.720

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fgf8
• 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); limbs/digits/tail phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory 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; reproductive system 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); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: fgf8a
• Affected structure: midbrain hindbrain boundary neural rod
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: MAPK cascade;branching involved in blood vessel morphogenesis;metanephros development;branching involved in ureteric bud morphogenesis;organ induction;mesonephros development;neural plate morphogenesis;heart looping;blood vessel remodeling;outflow tract septum morphogenesis;epithelial to mesenchymal transition involved in endocardial cushion formation;apoptotic process;response to oxidative stress;gastrulation;motor neuron axon guidance;mesodermal cell migration;positive regulation of cell population proliferation;gonad development;fibroblast growth factor receptor signaling pathway;anatomical structure morphogenesis;regulation of signaling receptor activity;positive regulation of gene expression;response to organic cyclic compound;peptidyl-tyrosine phosphorylation;pallium development;subpallium development;forebrain dorsal/ventral pattern formation;cell proliferation in forebrain;forebrain neuron development;signal transduction involved in regulation of gene expression;BMP signaling pathway;male genitalia development;thyroid gland development;otic vesicle formation;midbrain-hindbrain boundary development;dorsal/ventral axon guidance;embryonic hindlimb morphogenesis;aorta morphogenesis;phosphatidylinositol-3-phosphate biosynthetic process;odontogenesis;regulation of odontogenesis of dentin-containing tooth;response to drug;negative regulation of neuron apoptotic process;cell fate commitment;positive regulation of cell differentiation;positive regulation of G protein-coupled receptor signaling pathway;positive regulation of mitotic nuclear division;positive regulation of organ growth;phosphatidylinositol phosphorylation;forebrain morphogenesis;positive regulation of peptidyl-tyrosine phosphorylation;positive chemotaxis;positive regulation of cell division;positive regulation of protein kinase B signaling;negative regulation of cardiac muscle tissue development;pharyngeal system development;canonical Wnt signaling pathway;corticotropin hormone secreting cell differentiation;thyroid-stimulating hormone-secreting cell differentiation;bone development;lung morphogenesis;branching involved in salivary gland morphogenesis;neuroepithelial cell differentiation;positive regulation of ERK1 and ERK2 cascade;dopaminergic neuron differentiation;cell migration involved in mesendoderm migration
• Cellular component: extracellular region;external side of plasma membrane
• Molecular function: protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;fibroblast growth factor receptor binding;growth factor activity;1-phosphatidylinositol-3-kinase activity;chemoattractant activity;phosphatidylinositol-4,5-bisphosphate 3-kinase activity