FGF3

Summary

FGF3 (fibroblast growth factor 3, HGNC:3681) is a protein-coding gene on chromosome 11q13.3, encoding Fibroblast growth factor 3 (P11487). Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. In precision oncology, FGF3 Amplification confers sensitivity to Dovitinib in Breast Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below.

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation.

Source: NCBI Gene 2248 — RefSeq curated summary.

At a glance

• Gene–disease (curated): deafness with labyrinthine aplasia, microtia, and microdontia (Definitive, ClinGen)
• GWAS associations: 10
• Clinical variants (ClinVar): 164 total — 12 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 56
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_005247

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3681
Approved symbol	FGF3
Name	fibroblast growth factor 3
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	HBGF-3
Ensembl gene	ENSG00000186895
Ensembl biotype	protein_coding
OMIM	164950
Entrez	2248

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000334134, ENST00000646078

RefSeq mRNA: 1 — MANE Select: NM_005247 NM_005247

CCDS: CCDS8195

Canonical transcript exons

ENST00000334134 — 3 exons

Exon	Start	End
ENSE00001334973	69816320	69816423
ENSE00001335014	69809968	69810700
ENSE00001335016	69818714	69819416

Expression profiles

Bgee: expression breadth broad, 23 present calls, max score 83.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2073 / max 119.6645, expressed in 40 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121056	0.0765	21
121059	0.0489	6
121058	0.0469	3
121060	0.0202	4
121057	0.0148	3

Top tissues by expression

257 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	83.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.27	gold quality
cerebellar cortex	UBERON:0002129	83.13	gold quality
cerebellum	UBERON:0002037	81.17	gold quality
cerebellar vermis	UBERON:0004720	62.64	gold quality
myocardium	UBERON:0002349	60.09	gold quality
buccal mucosa cell	CL:0002336	59.67	gold quality
paraflocculus	UBERON:0005351	56.89	gold quality
parotid gland	UBERON:0001831	54.59	gold quality
vena cava	UBERON:0004087	53.78	gold quality
decidua	UBERON:0002450	53.58	gold quality
tendon of biceps brachii	UBERON:0008188	52.37	gold quality
nasal cavity epithelium	UBERON:0005384	51.49	gold quality
pons	UBERON:0000988	51.47	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.78	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
middle temporal gyrus	UBERON:0002771	49.37	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
quadriceps femoris	UBERON:0001377	49.14	gold quality
Brodmann (1909) area 46	UBERON:0006483	48.95	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
vastus lateralis	UBERON:0001379	48.57	gold quality
metanephric glomerulus	UBERON:0004736	47.83	gold quality
renal glomerulus	UBERON:0000074	47.64	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
endometrium epithelium	UBERON:0004811	46.85	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
thymus	UBERON:0002370	46.27	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTBP2, FOXP1, GATA4, LEF1, MYC, RUNX2, SOX2, SOX3, SOX6, SOX7, TFAP2A

miRNA regulators (miRDB)

11 targeting FGF3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-5088-5P	97.97	64.28	487
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Rac1, Rac2 and Mtl, have overlapping functions in the control of epithelial morphogenesis, myoblast fusion, and axon growth and guidance (PMID:11919634)
• axon growth, guidance and branching could be controlled by differential activation of Rac signalling pathways (PMID:11919635)
• Drac1 and Crumbs participate in amnioserosa morphogenesis during dorsal closure in Drosophila. (PMID:11973353)
• Rac1 is partially responsible for mediating the effect of Fmr1 on dendritic development. (PMID:14530299)
• Both Rac1 and Cdc42 activation induced large growth cones and long filopodia, but Cdc42 did so more efficiently than Rac1. Only Rac1 activation, however, induced thick actin bundles in the filopodia. (PMID:14750960)
• Rac plays multiple roles in epithelial sheet fusion, including dorsal closure. (PMID:15936337)
• Rac1 is involved in the regulation of myoblast proliferation and segregation during adult myogenesis. (PMID:16125691)
• regulation of cadherin-based adherens junctions by Rac is critical for salivary gland morphogenesis and that this regulation occurs through dynamin-mediated endocytosis (PMID:16412417)
• Rac1 induces Bsk activity and stable actin formation for cellular immune activation, leading to sessile hemocyte release and an increase in the number of circulating hemocytes. (PMID:16621891)
• These results reveal a role for chimaerin in the regulation of ERK signaling and cell-cell adhesion and have implications for its participation in epithelial development and tumor progression. (PMID:17438281)
• Rho GTPases may have partially overlapping functions during planar cell polarity generation (PMID:17616927)
• Reducing activity of the Egfr, Vav, or Rac1 from somatic support cells enhanced the germ cell enclosure defects of a conditional Spitz allele. (PMID:17629483)
• Recruitment of Cdc42 and Rac1 to the sites of filopodium and lamellipodium formation is Rab35 dependent and occurs by way of microtubule tracks. (PMID:20065041)
• Study reports that a small G protein Rac-dependent forgetting mechanism contributes to both passive memory decay and interference-induced forgetting in Drosophila. (PMID:20178749)
• Apical proteins including beta(H) are negatively regulated by Rac1 activation. (PMID:21111816)
• Rac may signal through Pak and LIMK to result in uniform phosphorylation of cofilin in all the outer border cells. (PMID:21205790)
• Data show that one of the two GEF domains of Trio, the Rac-specific GEF1, is essential for Trio-dependent motor axon guidance and for the genetic suppression of Notch function in motor axon patterning. (PMID:21246649)
• Mbc is crucial for the integrity of the F-actin foci and the FCM cytoskeleton, presumably via its activation of Rac1 in these cells. (PMID:21389053)
• These results suggest that Pak3 specifically mediates Rac1 signaling in organizing actin and myosin during Drosophila epidermal wound healing. (PMID:22449966)
• Rac is asymmetrically activated in germline stem cells. (PMID:22802725)
• alphaPS1betaPS integrin controls salivary gland migration through Rac1 GTPase which downregulates E-cadherin in proximal and distal gland cells. (PMID:23500171)
• The small GTPase RAC1 is a driver of intestinal stem cell proliferation through the production of reactive oxygen species. (PMID:23974108)
• identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glial responses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris (PMID:25099352)
• PERK/ATF4 activated the JNK pathway through Rac1 and Slpr activation in apoptotic cells. (PMID:25299777)
• We propose that the guanine nucleotide exchange factor GEFmeso is involved in a developmental process that requires the synergistic action of CDC42 and Rac1 during Drosophila development (PMID:25753922)
• Rac1, a small GTPase, is specifically required in Eiger-mediated cell death. rac1 loss of function blocks Eiger-induced cell death, whereas Rac1 overexpression enhances Eiger-induced killing. (PMID:27054336)
• Behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes. (PMID:27335463)
• The Abl tyrosine kinase signaling network controls cell migration, epithelial organization, axon patterning and other aspects of development. Abl suppresses the actin-regulatory factor Enabled, and we find that Abl also acts through the GEF Trio to stimulate the signaling activity of Rac GTPase. (PMID:28087633)
• BMP-dependent synaptic development requires Abi-Abl-Rac signaling of BMP receptor macropinocytosis (PMID:30737382)
• Rac1 expression in mushroom bodies regulates actin filament dynamics and acquisition of alcohol consumption preference. (PMID:31558618)
• Wnt6 regulates the homeostasis of the stem cell niche via Rac1-and Cdc42-mediated noncanonical Wnt signalling pathways in Drosophila testis. (PMID:33582096)
• Rac1 and Akt Exhibit Distinct Roles in Mediating Abeta-Induced Memory Damage and Learning Impairment. (PMID:34273104)
• These findings suggest that the nuclear form of FGF3 inhibits cell proliferation by interfering with ribosomal biogenesis. (PMID:16263090)
• Development of the inner ear is completely disturbed at a very early stage–or the otic vesicle is not induced at all–in all of the affected individuals who carried two mutant FGF3 alleles (PMID:17236138)
• FGF3, FGF7, FGF10, FGF18, and FGFR1 may have roles in nonsyndromic cleft lip and palate (PMID:17360555)
• Implication of FGF3 and FADD in human craniofacial disease. (PMID:17656375)
• sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. (PMID:18435799)
• study identified a homozygous missense mutation (c.196G–>T) in FGF3 in 21 affected individuals from a large extended family phenotypically characterized by autosomal recessive syndromic congenital sensorineural deafness, microtia and microdontia (PMID:18701883)
• Loss of FGFR3 signaling provides evidence that extracellular signals regulate not simply the proliferation or survival of radial glial cells, but specifically their progression to intermediate progenitor cells during neurogenesis in vivo. (PMID:19923290)
• labyrinth aplasia, microtia, and microdontia (LAMM) syndrome, caused by mutations in FGF3 (PMID:19950373)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf3	ENSDARG00000101540
mus_musculus	Fgf3	ENSMUSG00000031074
rattus_norvegicus	Fgf3	ENSRNOG00000020888

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF6 (ENSG00000111241), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF23 (ENSG00000118972), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 3 — P11487 (reviewed: P11487)

Alternative names: Heparin-binding growth factor 3, Proto-oncogene Int-2

All UniProt accessions (2): A0A7U3JVY0, P11487

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal ear development.

Subunit / interactions. Interacts with FGFR1 and FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.

Subcellular location. Secreted.

Disease relevance. Deafness with labyrinthine aplasia, microtia and microdontia (LAMM) [MIM:610706] Unique autosomal recessive syndrome characterized by type I microtia, microdontia, and profound congenital deafness associated with a complete absence of inner ear structures (Michel aplasia). The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the heparin-binding growth factors family.

RefSeq proteins (1): NP_005238* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (7 total): sequence variant 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11487-F1	79.32	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 65

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-190370	FGFR1b ligand binding and activation
R-HSA-190377	FGFR2b ligand binding and activation
R-HSA-2033519	Activated point mutants of FGFR2
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5655253	Signaling by FGFR2 in disease
R-HSA-5658623	FGFRL1 modulation of FGFR1 signaling
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling

MSigDB gene sets: 284 (showing top): MYAATNNNNNNNGGC_UNKNOWN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, HARRIS_HYPOXIA, GOBP_REGULATION_OF_CARDIAC_MUSCLE_TISSUE_DEVELOPMENT, NKX25_02, KEGG_MAPK_SIGNALING_PATHWAY, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, chr11q13, GOBP_CELL_CELL_SIGNALING

GO Biological Process (13): signal transduction (GO:0007165), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), anatomical structure morphogenesis (GO:0009653), neurogenesis (GO:0022008), regulation of cell migration (GO:0030334), positive regulation of MAPK cascade (GO:0043410), positive regulation of cell division (GO:0051781), negative regulation of cardiac muscle tissue development (GO:0055026), cell differentiation (GO:0030154), regulation of developmental process (GO:0050793), regulation of multicellular organismal process (GO:0051239)

GO Molecular Function (3): fibroblast growth factor receptor binding (GO:0005104), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
Downstream signaling of activated FGFR2	4
Signaling by FGFR1	3
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 ligand binding and activation	1
FGFR2 ligand binding and activation	1
FGFR2 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Signaling by FGFR2	1
Signaling by FGFR in disease	1
MAPK1/MAPK3 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
signaling	2
positive regulation of cellular process	2
developmental process	2
regulation of biological process	2
cellular anatomical structure	2
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
anatomical structure development	1
nervous system development	1
cell differentiation	1
cell migration	1
regulation of cell motility	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cell division	1
regulation of cell division	1
negative regulation of striated muscle tissue development	1
cardiac muscle tissue development	1
regulation of cardiac muscle tissue development	1
cellular developmental process	1
multicellular organismal process	1
growth factor receptor binding	1
receptor ligand activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF3	FGFR1	P11362	997
FGF3	EGF	P01133	989
FGF3	FGFR2	P18443	987
FGF3	KL	Q9UEF7	986
FGF3	FGFR4	P22455	983
FGF3	HSPG2	P98160	946
FGF3	FGFBP1	Q14512	940
FGF3	DCN	P07585	936
FGF3	FGFR3	P22607	932
FGF3	CDH2	P19022	879
FGF3	CD44	P16070	874
FGF3	HGF	P14210	871
FGF3	KLB	Q86Z14	844
FGF3	SHH	Q15465	841
FGF3	NRP1	O14786	824

IntAct

13 interactions, top by confidence:

A	B	Type	Score
FGF3	GTPBP10	psi-mi:“MI:0914”(association)	0.530
	FGF3	psi-mi:“MI:0407”(direct interaction)	0.440
FBXW7	FGF3	psi-mi:“MI:2364”(proximity)	0.270
FGF3	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SPOP	FGF3	psi-mi:“MI:2364”(proximity)	0.270
FGF3	SPOP	psi-mi:“MI:2364”(proximity)	0.270
EGFR	FGF3	psi-mi:“MI:2364”(proximity)	0.270
FGF3	PTEN	psi-mi:“MI:2364”(proximity)	0.270
FGF3	AKT1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (96): FGF3 (Protein-peptide), FGF3 (Protein-peptide), ANKHD1-EIF4EBP3 (Affinity Capture-MS), XRN1 (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), ZNF100 (Affinity Capture-MS), ZNF593 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), NUCB1 (Affinity Capture-MS), CDKN2AIP (Affinity Capture-MS), GTPBP10 (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), URB1 (Affinity Capture-MS), TMED1 (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, P03968, P03969, P05230, P05524, P08620, P09038, P10767, P11403, P11487, P12034, P12226, P13109, P15655, P15656, P19596, P20002, P20003, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P48798, P48799, P48800, P48801, P48802, P48803, P48804, P48805, P48806

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FGF3	up-regulates	FGFR2	binding

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

FGF3 is a member of the basic fibroblast growth factor (FGF) gene family and was first identified based on it’s similarity to the mouse proto-oncogene int-2. Amplifications of this gene and the surrounding region (11q13) have been observed in various cancers including breast cancer, esophogeal cancer, melanoma, bladder cancer and hepatocellular carcinoma (HCC). Lower tumor grade and stage have been associated with FGF3 amplifications in HCC; however, this event is fairly rare in this tumor type.

Clinical variants and AI predictions

ClinVar

164 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	10
Uncertain significance	76
Likely benign	34
Benign	14

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
13837	NM_005247.4(FGF3):c.466T>C (p.Ser156Pro)	Pathogenic
13839	NM_005247.4(FGF3):c.616del (p.Val206fs)	Pathogenic
13841	NM_005247.4(FGF3):c.17T>C (p.Leu6Pro)	Pathogenic
13842	NM_005247.4(FGF3):c.255del (p.Ile85fs)	Pathogenic
2844855	NM_005247.4(FGF3):c.355G>T (p.Glu119Ter)	Pathogenic
29817	NM_005247.4(FGF3):c.317A>G (p.Tyr106Cys)	Pathogenic
29818	NM_005247.4(FGF3):c.457_458del (p.Trp153fs)	Pathogenic
3244763	NC_000011.9:g.(?69625073)(69633701_?)del	Pathogenic
3601129	NM_005247.4(FGF3):c.63del (p.Ala23fs)	Pathogenic
3615027	NM_005247.4(FGF3):c.318T>A (p.Tyr106Ter)	Pathogenic
4083369	NM_005247.4(FGF3):c.2T>G (p.Met1Arg)	Pathogenic
417891	NM_005247.4(FGF3):c.270dup (p.Leu91fs)	Pathogenic
13840	NM_005247.4(FGF3):c.196G>T (p.Gly66Cys)	Likely pathogenic
1677104	NM_005247.4(FGF3):c.431del (p.Arg144fs)	Likely pathogenic
2015207	NM_005247.4(FGF3):c.221-1G>C	Likely pathogenic
3352425	NM_005247.4(FGF3):c.265del (p.Arg89fs)	Likely pathogenic
3376260	NM_005247.4(FGF3):c.269del (p.Gly90fs)	Likely pathogenic
3601125	NM_005247.4(FGF3):c.220+1G>A	Likely pathogenic
3601127	NM_005247.4(FGF3):c.470T>C (p.Val157Ala)	Likely pathogenic
3601128	NM_005247.4(FGF3):c.517C>T (p.Gln173Ter)	Likely pathogenic
4072154	NM_005247.4(FGF3):c.284G>A (p.Arg95Gln)	Likely pathogenic
627444	NM_005247.4(FGF3):c.462C>G (p.Tyr154Ter)	Likely pathogenic

SpliceAI

439 predictions. Top by Δscore:

Variant	Effect	Δscore
11:69810696:TGCTC:T	acceptor_gain	1.0000
11:69810698:CTC:C	acceptor_gain	1.0000
11:69810699:TC:T	acceptor_gain	1.0000
11:69810700:CC:C	acceptor_gain	1.0000
11:69810701:C:CC	acceptor_gain	1.0000
11:69810701:CT:C	acceptor_loss	1.0000
11:69810702:T:A	acceptor_loss	1.0000
11:69810704:C:CT	acceptor_gain	1.0000
11:69816313:GACT:G	donor_loss	1.0000
11:69816314:ACT:A	donor_loss	1.0000
11:69816315:CTCA:C	donor_loss	1.0000
11:69816316:TCA:T	donor_loss	1.0000
11:69816317:CA:C	donor_loss	1.0000
11:69818712:A:AC	donor_gain	1.0000
11:69818713:C:CA	donor_gain	1.0000
11:69810697:GCTC:G	acceptor_gain	0.9900
11:69810698:CTCC:C	acceptor_gain	0.9900
11:69810699:TCCT:T	acceptor_gain	0.9900
11:69810705:G:T	acceptor_gain	0.9900
11:69816312:GGAC:G	donor_loss	0.9900
11:69816318:A:AC	donor_gain	0.9900
11:69816319:C:CC	donor_gain	0.9900
11:69816421:TAC:T	acceptor_gain	0.9900
11:69816423:CCTAG:C	acceptor_loss	0.9900
11:69816425:T:C	acceptor_loss	0.9900
11:69818707:CACT:C	donor_loss	0.9900
11:69818710:TCA:T	donor_loss	0.9900
11:69818711:CA:C	donor_loss	0.9900
11:69818713:CT:C	donor_gain	0.9900
11:69818713:CTG:C	donor_gain	0.9900

AlphaMissense

1509 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:69810492:A:G	F178S	1.000
11:69810675:A:C	F117C	1.000
11:69810675:A:G	F117S	1.000
11:69810491:G:C	F178L	0.999
11:69810491:G:T	F178L	0.999
11:69810492:A:C	F178C	0.999
11:69810493:A:G	F178L	0.999
11:69810543:C:T	G161D	0.999
11:69810640:A:C	Y129D	0.999
11:69810640:A:G	Y129H	0.999
11:69810668:C:A	E119D	0.999
11:69810668:C:G	E119D	0.999
11:69810669:T:A	E119V	0.999
11:69816336:C:A	G103V	0.999
11:69816336:C:T	G103E	0.999
11:69816381:A:T	I88N	0.999
11:69818737:C:T	G66D	0.999
11:69818767:A:G	L56P	0.999
11:69818767:A:T	L56H	0.999
11:69818784:G:C	C50W	0.999
11:69818785:C:T	C50Y	0.999
11:69810486:G:T	P180H	0.998
11:69810493:A:C	F178V	0.998
11:69810543:C:A	G161V	0.998
11:69810544:C:G	G161R	0.998
11:69810559:A:G	S156P	0.998
11:69810640:A:T	Y129N	0.998
11:69810644:A:C	N127K	0.998
11:69810644:A:T	N127K	0.998
11:69810666:C:G	R120P	0.998

dbSNP variants (sampled 300 via entrez): RS1000421050 (11:69817882 C>A,T), RS1000473324 (11:69818055 C>G), RS1000968353 (11:69814279 G>A), RS1001991427 (11:69811628 T>C), RS1003164393 (11:69814346 T>G), RS1003657097 (11:69820529 G>A), RS1003913281 (11:69810956 G>A), RS1004218838 (11:69815961 A>G), RS1004231989 (11:69820844 G>A,T), RS1004375068 (11:69815986 G>A), RS1004481058 (11:69810585 G>C), RS1004870005 (11:69811965 C>T), RS1005596029 (11:69809880 G>A), RS1005897139 (11:69819748 G>T), RS1006614896 (11:69817569 C>G)

Disease associations

OMIM: gene MIM:164950 | disease phenotypes: MIM:610706

GenCC curated gene-disease

Disease	Classification	Inheritance
deafness with labyrinthine aplasia, microtia, and microdontia	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
deafness with labyrinthine aplasia, microtia, and microdontia	Definitive	AR

Mondo (2): deafness with labyrinthine aplasia, microtia, and microdontia (MONDO:0012541), hearing loss disorder (MONDO:0005365)

Orphanet (1): Deafness with labyrinthine aplasia, microtia, and microdontia (Orphanet:90024)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000098	Tall stature
HP:0000212	Gingival overgrowth
HP:0000276	Long face
HP:0000293	Full cheeks
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000326	Abnormal maxilla morphology
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000480	Retinal coloboma
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000189_4	Protein quantitative trait loci	1.000000e-07
GCST000678_13	Breast cancer	3.000000e-15
GCST002829_16	Urate levels in overweight individuals	8.000000e-07
GCST003991_9	Childhood ear infection	3.000000e-09
GCST003996_10	Monobrow	5.000000e-12
GCST004412_6	Craniofacial microsomia	4.000000e-17
GCST005013_44	Childhood ear infection	3.000000e-09
GCST005976_8	White blood cell count (basophil)	4.000000e-08
GCST008153_5	Lean body mass	6.000000e-06
GCST012597_3	Attention deficit hyperactivity disorder	7.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004754	interleukin 1 receptor antagonist measurement
EFO:0004531	urate measurement
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0007906	synophrys measurement
EFO:0005090	basophil count
EFO:0004995	lean body mass

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C565195	Deafness, Congenital, with Inner Ear Agenesis, Microtia, and Microdontia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
FGF3 Amplification	Dovitinib	Breast Cancer	Sensitivity/Response	CIViC B	EID1606
FGF3 Amplification	Sorafenib	Hepatocellular Carcinoma	Sensitivity/Response	CIViC C	EID1966

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects binding, increases reaction	2
taxifolin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	increases expression	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects binding, increases expression	1
Phthalic Acids	decreases methylation	1
Valproic Acid	increases methylation	1
Magnetite Nanoparticles	decreases methylation	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss