FGF23

fibroblast growth factor 23, the group of Receptor ligands|Fibroblast growth factor family

Basic information

Region (hg38): 12:4368226-4379712

Links

ENSG00000118972 ∙ NCBI:8074 ∙ OMIM:605380 ∙ HGNC:3680 ∙ Uniprot:Q9GZV9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• tumoral calcinosis, hyperphosphatemic, familial, 2 (Strong), mode of inheritance: AR
• tumoral calcinosis, hyperphosphatemic, familial, 2 (Moderate), mode of inheritance: AR
• autosomal dominant hypophosphatemic rickets (Moderate), mode of inheritance: AD
• autosomal dominant hypophosphatemic rickets (Supportive), mode of inheritance: AD
• tumoral calcinosis, hyperphosphatemic, familial, 1 (Supportive), mode of inheritance: AR
• autosomal dominant hypophosphatemic rickets (Strong), mode of inheritance: AD
• tumoral calcinosis, hyperphosphatemic, familial, 2 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypophosphatemic rickets, autosomal dominant; Tumoral calcinosis, hyperphosphatemic, familial, 2	AD/AR	Renal	In Hypophosphatemic rickets, autosomal dominant, treatment with both phosphate and high-dose vitamin D can be effective; In Tumoral calcinosis, hyperphosphatemic, phosphate reduction (eg, with dietary means and phosphate-binding agents) can be beneficial	Dental; Renal; Musculoskeletal	5925614; 5173181; 4538804; 4353218; 3659264; 2777854; 1353055; 9024275; 11062477; 12541190; 15590700

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FGF23 gene.

• not provided (99 variants)
• Autosomal dominant hypophosphatemic rickets (60 variants)
• Tumoral calcinosis, hyperphosphatemic, familial, 2 (58 variants)
• Autosomal dominant hypophosphatemic rickets;Tumoral calcinosis, hyperphosphatemic, familial, 2 (10 variants)
• Inborn genetic diseases (10 variants)
• Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome (9 variants)
• Hypophosphatemic Rickets, Dominant (7 variants)
• not specified (5 variants)
• Tumoral calcinosis, hyperphosphatemic, familial, 2;Autosomal dominant hypophosphatemic rickets (5 variants)
• Tumoral calcinosis, hyperphosphatemic, familial, 1 (3 variants)
• Hypophosphatemia (1 variants)
• Hypophosphatemic rickets (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FGF23 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			4	21		25
missense	4	4	51	1	1	61
nonsense			1			1
start loss						0
frameshift			1			1
inframe indel		1	1			2
splice donor/acceptor (+/-2bp)						0
splice region			2	1		3
non coding			30	12	16	58
Total	4	5	88	34	17

Highest pathogenic variant AF is 0.00000658

Variants in FGF23

This is a list of pathogenic ClinVar variants found in the FGF23 region.

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

Position	Type	Phenotype	Significance	ClinVar
12-4368281-T-G		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Benign/Likely benign (Jan 13, 2018)
12-4368372-A-G		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Benign (Jan 12, 2018)
12-4368418-T-C		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Uncertain significance (Jan 13, 2018)
12-4368457-G-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Conflicting classifications of pathogenicity (Jan 13, 2018)
12-4368540-G-A		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Conflicting classifications of pathogenicity (Jan 12, 2018)
12-4368571-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Conflicting classifications of pathogenicity (Jan 13, 2018)
12-4368768-A-G		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 13, 2018)
12-4368795-A-C		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Uncertain significance (Jan 13, 2018)
12-4368851-A-G		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 13, 2018)
12-4368872-G-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Benign (Jan 12, 2018)
12-4368879-A-G		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Benign (Jan 12, 2018)
12-4368914-T-A		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Benign (May 11, 2021)
12-4368945-A-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Conflicting classifications of pathogenicity (Jan 13, 2018)
12-4368957-GGAA-G		Hypophosphatemic Rickets, Dominant • Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome	Uncertain significance (Jun 14, 2016)
12-4368991-A-G		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 12, 2018)
12-4369027-G-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Benign (Jan 13, 2018)
12-4369051-G-A		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 13, 2018)
12-4369124-G-A		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Benign (Jan 13, 2018)
12-4369209-T-A		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Uncertain significance (Jan 12, 2018)
12-4369264-T-C		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Benign (Jan 12, 2018)
12-4369294-G-A		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 12, 2018)
12-4369345-G-C		Autosomal dominant hypophosphatemic rickets • Tumoral calcinosis, hyperphosphatemic, familial, 2	Likely benign (Apr 28, 2017)
12-4369399-C-T		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 13, 2018)
12-4369487-G-C		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 12, 2018)
12-4369559-G-A		Tumoral calcinosis, hyperphosphatemic, familial, 2 • Autosomal dominant hypophosphatemic rickets	Uncertain significance (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FGF23	protein_coding	protein_coding	ENST00000237837	3	11502

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0310	0.824	125733	0	5	125738	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.398	150	164	0.913	0.0000112	1640
Missense in Polyphen		41	54.532	0.75185		547
Synonymous	1.49	58	74.4	0.780	0.00000557	521
Loss of Function	1.14	3	6.01	0.499	2.59e-7	77

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization. {ECO:0000250, ECO:0000269|PubMed:11062477, ECO:0000269|PubMed:11409890, ECO:0000269|PubMed:15040831, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:18282132}.
• Disease: DISEASE: Hypophosphatemic rickets, autosomal dominant (ADHR) [MIM:193100]: A disease characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25- dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. {ECO:0000269|PubMed:11062477, ECO:0000269|PubMed:11409890, ECO:0000269|PubMed:16638743}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tumoral calcinosis, hyperphosphatemic, familial, 2 (HFTC2) [MIM:617993]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269|PubMed:15590700, ECO:0000269|PubMed:16030159, ECO:0000269|PubMed:16151858, ECO:0000269|PubMed:24680727}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• 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);Vitamin D Receptor Pathway;Osteoblast Signaling;MAPK Signaling Pathway;ESC Pluripotency Pathways;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;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;Post-translational protein phosphorylation;FGFR3 mutant receptor activation;Post-translational protein modification;PI3K Cascade;IRS-mediated signalling;Insulin receptor signalling cascade;Activated point mutants of FGFR2;Signaling by Insulin receptor;Metabolism of proteins;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;FGF;Signaling by FGFR2 in disease;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);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;Syndecan-1-mediated signaling events;Downstream signaling of activated FGFR1;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);FGFR1c ligand binding and activation;FGF signaling pathway;FGFR1c and Klotho ligand binding and activation;FGFR1 ligand binding and activation;Syndecan-2-mediated signaling events;FGFRL1 modulation of FGFR1 signaling;Syndecan-3-mediated signaling events;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: 0.347

Intolerance Scores

• loftool: 0.175
• rvis_EVS: 0.08
• rvis_percentile_EVS: 60.09

Haploinsufficiency Scores

• pHI: 0.494
• hipred: N
• hipred_score: 0.330
• ghis: 0.400

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0308

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fgf23
• 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); growth/size/body region phenotype; endocrine/exocrine gland phenotype; immune system phenotype; homeostasis/metabolism phenotype; renal/urinary system phenotype; skeleton phenotype; 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); 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); limbs/digits/tail phenotype; digestive/alimentary phenotype

Zebrafish Information Network

• Gene name: fgf23
• Affected structure: calcium ion import
• Phenotype tag: abnormal
• Phenotype quality: increased occurrence

Gene ontology

• Biological process: MAPK cascade;fibroblast growth factor receptor signaling pathway;regulation of signaling receptor activity;regulation of phosphate transport;positive regulation of vitamin D 24-hydroxylase activity;peptidyl-tyrosine phosphorylation;cell differentiation;negative regulation of bone mineralization;cellular phosphate ion homeostasis;response to magnesium ion;phosphatidylinositol-3-phosphate biosynthetic process;vitamin D catabolic process;post-translational protein modification;cellular protein metabolic process;cellular response to leptin stimulus;negative regulation of osteoblast differentiation;positive regulation of transcription, DNA-templated;phosphatidylinositol phosphorylation;negative regulation of hormone secretion;positive regulation of protein kinase B signaling;phosphate ion homeostasis;positive regulation of ERK1 and ERK2 cascade;cellular response to vitamin D;cellular response to interleukin-6;cellular response to parathyroid hormone stimulus;positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway;response to sodium phosphate
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;Golgi lumen
• Molecular function: protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;type 1 fibroblast growth factor receptor binding;protein binding;growth factor activity;1-phosphatidylinositol-3-kinase activity;phosphatidylinositol-4,5-bisphosphate 3-kinase activity