GeneBe

FGFR4

protein-coding

fibroblast growth factor receptor 4, the group of Receptor tyrosine kinases|CD molecules|I-set domain containing

Gene summary

The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

MANE transcript

NM_213647.3

Inheritance

—

ClinVar variants

U:126B:18

Top phenotype

FGFR4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr5:177,086,905-177,098,144

External References & Databases

Ensembl (ENSG00000160867)NCBI Gene (2264)OMIM (134935)HGNC:3691GenCCUniProt (P22455)AlphaFoldClinVar (FGFR4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.2 kb
Loading mutation effect viewer...

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 FGFR4 variants in ClinVar

3 Conditions Cataloged
not specifiedTotal: 105
not providedTotal: 9
FGFR4-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_213647.3. 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
10
clinvar
2
clinvar
 17
missense
119
clinvar
4
clinvar
2
clinvar
 125
nonsense
0
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total00126144144
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 117 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_213647.3RefSeqNP_998812.117MANE Select
ENST00000292408.9EnsemblENSP00000292408.417MANE Select
NM_001291980.2RefSeqNP_001278909.117Standard
NM_001354984.2RefSeqNP_001341913.117Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fgfr4Danio rerio

Structure: solid lens vesicle

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Endocytosis - Homo sapiens (human)
  • Regulation of actin cytoskeleton - Homo sapiens (human)
  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Rap1 signaling pathway - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • nervous system development
  • positive regulation of cell population proliferation
  • fibroblast growth factor receptor signaling pathway

Molecular Function

  • protein tyrosine kinase activity
  • transmembrane receptor protein tyrosine kinase activity
  • fibroblast growth factor-activated receptor activity
  • Ras guanyl-nucleotide exchange factor activity
  • protein binding

Cellular Component

  • extracellular region
  • endosome
  • endoplasmic reticulum
  • Golgi apparatus
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000292408
Coding exons
17
Length
11259
Individuals with no LoFs
125677
Homozygous LoFs
0
Heterozygous LoFs
71
Defined
125748
p
0.000282
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.194515280.8550.00003645085
Missense (PolyPhen)170250.50.678632531
Synonymous-0.6932492351.060.00001681738
Loss of Function2.242641.50.6260.00000249413

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000200.00018rare
Latino/Admixed American0.000180.00017rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000220.00022rare
Finnish0.0000510.000046rare
European (Non-Finnish)0.000430.00041rare
South Asian0.000200.00020rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}.;
Disease
DISEASE: Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21349172}. Note=The gene represented in this entry is involved in disease pathogenesis. FGFR4 variant Arg-388 has been associated with prostate cancer as well as cancers of the breast, colon, head and neck, larynx, lung, skin. Arg-388 predisposes cancer patients for accelerated disease progression and is associated with poor prognosis. {ECO:0000269|PubMed:11781352, ECO:0000269|PubMed:11830541, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523, ECO:0000269|PubMed:20638838, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21349172, ECO:0000269|PubMed:21412156, ECO:0000269|PubMed:21882254, ECO:0000269|PubMed:26675719}.;

Recessive Scores

pRec
0.316

Intolerance Scores

LoFtool
0.0501
RVIS EVS
-1.17
RVIS percentile EVS
6.07

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.914

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerHighMediumHigh
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