FGFR4

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

Basic information

Region (hg38): 5:177086904-177098144

Links

ENSG00000160867 ∙ NCBI:2264 ∙ OMIM:134935 ∙ HGNC:3691 ∙ Uniprot:P22455 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FGFR4 gene.

• Inborn genetic diseases (24 variants)
• not provided (9 variants)
• Cancer progression and tumor cell motility (1 variants)
• not specified (1 variants)
• See cases (1 variants)
• Classic Hodgkin lymphoma (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FGFR4 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				2	2	4
missense			23	2	2	27
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				2	1	3
non coding						0
Total	0	0	23	4	4

Variants in FGFR4

This is a list of pathogenic ClinVar variants found in the FGFR4 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-177089630-G-A		FGFR4-related disorder	Benign (Jul 15, 2020)
5-177089646-C-G		not specified	Uncertain significance (Mar 01, 2023)
5-177090392-C-T		not specified	Uncertain significance (Jun 23, 2021)
5-177090419-C-A		not specified	Uncertain significance (Oct 03, 2023)
5-177090460-T-G		FGFR4-related disorder	Benign (Oct 17, 2019)
5-177090558-A-T		not specified	Uncertain significance (Mar 07, 2024)
5-177090590-C-T		not specified	Uncertain significance (Sep 21, 2023)
5-177090796-C-T		Classic Hodgkin lymphoma • FGFR4-related disorder	Benign/Likely benign (Oct 01, 2021)
5-177090798-T-C		not specified	Uncertain significance (Jan 17, 2024)
5-177090800-G-A			Benign (Jul 31, 2018)
5-177091036-A-G		FGFR4-related disorder	Benign (Mar 28, 2019)
5-177091069-G-A		not specified	Uncertain significance (Jun 07, 2023)
5-177091087-C-T		not specified	Uncertain significance (Sep 01, 2021)
5-177091736-C-T		not specified	Uncertain significance (Sep 16, 2021)
5-177091737-G-A		not specified	Uncertain significance (May 04, 2023)
5-177091765-C-T			Benign (Jun 12, 2018)
5-177091766-G-A		not specified	Uncertain significance (Dec 07, 2021)
5-177091781-C-T		not specified	Uncertain significance (Oct 14, 2021)
5-177091783-C-T		FGFR4-related disorder	Benign (Oct 17, 2019)
5-177091793-C-A		not specified	Uncertain significance (May 10, 2023)
5-177092323-C-T		not specified	Uncertain significance (Dec 13, 2022)
5-177092331-G-A		FGFR4-related disorder	Likely benign (Jul 10, 2019)
5-177092360-C-T		not specified	Uncertain significance (Feb 12, 2024)
5-177092384-G-A		not specified	Uncertain significance (Dec 19, 2022)
5-177092484-C-T		FGFR4-related disorder	Likely benign (Feb 21, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FGFR4	protein_coding	protein_coding	ENST00000292408	17	11259

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.19e-13	0.957	125677	0	71	125748	0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.19	451	528	0.855	0.0000364	5085
Missense in Polyphen		170	250.5	0.67863		2531
Synonymous	-0.693	249	235	1.06	0.0000168	1738
Loss of Function	2.24	26	41.5	0.626	0.00000249	413

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000374	0.000361
Ashkenazi Jewish	0.000200	0.000198
East Asian	0.000222	0.000217
Finnish	0.0000513	0.0000462
European (Non-Finnish)	0.000429	0.000413
Middle Eastern	0.000222	0.000217
South Asian	0.000205	0.000196
Other	0.000334	0.000326

dbNSFP

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}.
• Pathway: 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);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Vemurafenib Pathway, Pharmacodynamics;update your name in edit mode;VEGF Signaling Pathway;Pathways Affected in Adenoid Cystic Carcinoma;MAPK Signaling Pathway;ESC Pluripotency Pathways;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Ras Signaling;Regulation of Actin Cytoskeleton;PI-3K cascade:FGFR4;Disease;betaKlotho-mediated ligand binding;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;PI3K Cascade;IRS-mediated signalling;Insulin receptor signalling cascade;Signaling by Insulin receptor;FGF;FGFR4 mutant receptor activation;Fibroblast growth factor-1;IL-7 signaling;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;JAK STAT pathway and regulation;EPO signaling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Signaling by FGFR4 in disease;Signaling by FGFR in disease;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;IRS-related events triggered by IGF1R;IGF1R signaling cascade;Signaling by Receptor Tyrosine Kinases;VEGF;Intracellular signaling by second messengers;Diseases of signal transduction;Syndecan-1-mediated signaling events;Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R);FGF signaling pathway;Syndecan-2-mediated signaling events;Syndecan-3-mediated signaling events;Phospholipase C-mediated cascade; FGFR4 (Consensus)

Recessive Scores

• pRec: 0.316

Intolerance Scores

• loftool: 0.0501
• rvis_EVS: -1.17
• rvis_percentile_EVS: 6.07

Haploinsufficiency Scores

• pHI: 0.939
• hipred: Y
• hipred_score: 0.747
• ghis: 0.470

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.914

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fgfr4
• Phenotype: neoplasm; hematopoietic system phenotype; reproductive 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); respiratory system phenotype; skeleton phenotype; immune system phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: fgfr4
• Affected structure: solid lens vesicle
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• 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;positive regulation of gene expression;regulation of extracellular matrix disassembly;cell migration;peptidyl-tyrosine phosphorylation;regulation of lipid metabolic process;phosphatidylinositol-3-phosphate biosynthetic process;glucose homeostasis;cholesterol homeostasis;positive regulation of catalytic activity;positive regulation of proteolysis;protein autophosphorylation;phosphatidylinositol phosphorylation;positive regulation of protein kinase B signaling;phosphate ion homeostasis;positive regulation of ERK1 and ERK2 cascade;regulation of bile acid biosynthetic process;response to bile acid;positive regulation of DNA biosynthetic process
• Cellular component: extracellular region;endosome;endoplasmic reticulum;Golgi apparatus;plasma membrane;integral component of plasma membrane;cell-cell junction;transport vesicle;receptor complex
• 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;ATP binding;heparin binding;1-phosphatidylinositol-3-kinase activity;fibroblast growth factor binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity