GeneBe

FGF23

protein-coding

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

Gene summary

This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC). [provided by RefSeq, Feb 2013]

MANE transcript

NM_020638.3

Inheritance

AD, AR

ClinVar variants

P:14U:134B:49

Top phenotype

Hypophosphatemic rickets, autosomal dominant; Tumoral calcinosis, hyperphosphatemic, familial, 2

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr12:4,368,227-4,379,712

External References & Databases

Ensembl (ENSG00000118972)NCBI Gene (8074)OMIM (605380)HGNC:3680GenCCUniProt (Q9GZV9)AlphaFoldClinVar (FGF23)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant hypophosphatemic ricketsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008660

Submitter: PanelApp Australia

tumoral calcinosis, hyperphosphatemic, familial, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060714

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant hypophosphatemic ricketsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008660

Submitter: Labcorp Genetics (formerly Invitae)

tumoral calcinosis, hyperphosphatemic, familial, 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008897

Submitter: Orphanet

autosomal dominant hypophosphatemic ricketsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008660

Submitter: Orphanet

tumoral calcinosis, hyperphosphatemic, familial, 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060714

Submitter: Ambry Genetics

autosomal dominant hypophosphatemic ricketsMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008660

Submitter: Ambry Genetics

tumoral calcinosis, hyperphosphatemic, familial, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060714

Submitter: Genomics England PanelApp

familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100251

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypophosphatemic rickets, autosomal dominant; Tumoral calcinosis, hyperphosphatemic, familial, 2AD/AR

Manifestation: Dental; Renal; Musculoskeletal

Intervention: Renal

Rationale: 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

Refs: 5925614; 5173181; 4538804; 4353218; 3659264; 2777854; 1353055; 9024275; 11062477; 12541190; 15590700Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FGF23 variants in ClinVar

11 Conditions Cataloged
not providedTotal: 166
Autosomal dominant hypophosphatemic ricketsTotal: 60
Tumoral calcinosis, hyperphosphatemic, familial, 2Total: 57
Inborn genetic diseasesTotal: 38
not specifiedTotal: 25
FGF23-related disorderTotal: 5
Tumoral calcinosis, hyperphosphatemic, familial, 1Total: 3
Familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020638.3. 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.

EffectPLPVUSLBBSum
synonymous
5
clinvar
43
clinvar
 48
missense
6
clinvar
6
clinvar
122
clinvar
6
clinvar
 140
nonsense
1
clinvar
3
clinvar
 4
start loss
0
frameshift
4
clinvar
 4
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total68134490197

Highest pathogenic variant AF is 0.000039112554

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_020638.3RefSeqNP_065689.13MANE Select
ENST00000237837.2EnsemblENSP00000237837.13MANE Select
ENST00001141862.1EnsemblENSP00000802169.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fgf23Danio rerio

Structure: calcium ion import

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

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

Molecular Function

  • protein tyrosine kinase activity
  • Ras guanyl-nucleotide exchange factor activity
  • type 1 fibroblast growth factor receptor binding
  • protein binding
  • growth factor activity

Cellular Component

  • extracellular region
  • extracellular space
  • endoplasmic reticulum lumen
  • Golgi lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000237837
Coding exons
3
Length
11502
Individuals with no LoFs
125733
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125738
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.3981501640.9130.00001121640
Missense (PolyPhen)4154.5320.75185547
Synonymous1.495874.40.7800.00000557521
Loss of Function1.1436.010.4992.59e-777

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.347

Intolerance Scores

LoFtool
0.175
RVIS EVS
0.08
RVIS percentile EVS
60.09

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0308

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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