EBF3

Summary

EBF3 (EBF transcription factor 3, HGNC:19087) is a protein-coding gene on chromosome 10q26.3, encoding Transcription factor COE3 (Q9H4W6). Transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the early B-cell factor (EBF) family of DNA binding transcription factors. EBF proteins are involved in B-cell differentiation, bone development and neurogenesis, and may also function as tumor suppressors. The encoded protein inhibits cell survival through the regulation of genes involved in cell cycle arrest and apoptosis, and aberrant methylation or deletion of this gene may play a role in multiple malignancies including glioblastoma multiforme and gastric carcinoma.

Source: NCBI Gene 253738 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotonia, ataxia, and delayed development syndrome (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 355 total — 62 pathogenic, 49 likely-pathogenic
• Phenotypes (HPO): 142
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001375380

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19087
Approved symbol	EBF3
Name	EBF transcription factor 3
Location	10q26.3
Locus type	gene with protein product
Status	Approved
Aliases	COE3, DKFZp667B0210
Ensembl gene	ENSG00000108001
Ensembl biotype	protein_coding
OMIM	607407
Entrez	253738

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000355311, ENST00000368648, ENST00000440978, ENST00000675373, ENST00000682649, ENST00000904893, ENST00000962323

RefSeq mRNA: 7 — MANE Select: NM_001375380 NM_001005463, NM_001375379, NM_001375380, NM_001375389, NM_001375390, NM_001375391, NM_001375392

CCDS: CCDS31314, CCDS91376, CCDS91377

Canonical transcript exons

ENST00000440978 — 17 exons

Exon	Start	End
ENSE00000728606	129840844	129841032
ENSE00000728631	129873452	129873596
ENSE00000874296	129840245	129840442
ENSE00001447659	129839083	129839195
ENSE00001638736	129848392	129848480
ENSE00001657573	129962942	129963005
ENSE00001660914	129962171	129962226
ENSE00001691761	129867141	129867267
ENSE00001701332	129867782	129867912
ENSE00001715366	129842116	129842293
ENSE00001740731	129877768	129877849
ENSE00001785574	129835233	129837960
ENSE00002436760	129963367	129963523
ENSE00002473636	129843137	129843202
ENSE00002497705	129957258	129957326
ENSE00002513504	129958934	129959007
ENSE00003898363	129963635	129964274

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 85.97.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8236 / max 148.7182, expressed in 687 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112043	2.7913	598
112042	0.3276	168
112041	0.2664	136
112045	0.1604	75
112035	0.1600	68
112044	0.1180	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	85.97	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.94	gold quality
tendon of biceps brachii	UBERON:0008188	85.82	silver quality
calcaneal tendon	UBERON:0003701	85.45	gold quality
adipose tissue	UBERON:0001013	84.84	gold quality
tendon	UBERON:0000043	84.73	gold quality
layer of synovial tissue	UBERON:0007616	83.80	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.60	gold quality
sural nerve	UBERON:0015488	82.53	gold quality
omental fat pad	UBERON:0010414	82.34	gold quality
peritoneum	UBERON:0002358	82.27	gold quality
synovial joint	UBERON:0002217	82.25	gold quality
tibial nerve	UBERON:0001323	80.28	gold quality
deltoid	UBERON:0001476	80.16	silver quality
hindlimb stylopod muscle	UBERON:0004252	79.19	gold quality
trabecular bone tissue	UBERON:0002483	78.86	gold quality
right atrium auricular region	UBERON:0006631	78.11	gold quality
cardiac atrium	UBERON:0002081	77.90	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.86	gold quality
muscle of leg	UBERON:0001383	77.64	gold quality
lymph node	UBERON:0000029	77.47	gold quality
buccal mucosa cell	CL:0002336	77.24	silver quality
gastrocnemius	UBERON:0001388	77.01	gold quality
apex of heart	UBERON:0002098	77.00	gold quality
tibia	UBERON:0000979	76.72	gold quality
skeletal muscle tissue	UBERON:0001134	76.54	gold quality
heart	UBERON:0000948	76.24	gold quality
skin of hip	UBERON:0001554	76.21	gold quality
heart left ventricle	UBERON:0002084	76.09	gold quality
cardiac ventricle	UBERON:0002082	75.82	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	325.15
E-CURD-112	yes	8.84
E-ANND-3	yes	7.09
E-MTAB-6058	no	48.09

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ACKR3
CDKN1A	Activation
HMGN3
IGF1
LGI1
LMO3
PLPP1
SLC12A5
SLIT2

JASPAR motifs

Motif	Name	Family
MA1637.1	EBF3	Early B-Cell Factor-related factors
MA1637.2	EBF3	Early B-Cell Factor-related factors

JASPAR matrix evidence (PMIDs): PMID:20592035

Upstream regulators (CollecTRI, top): ARX

miRNA regulators (miRDB)

219 targeting EBF3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• Expression of EBF3 resulted in cell cycle arrest and apoptosis. EBF3 regulates a transcriptional program underlying a putative tumor suppression pathway. (PMID:17018599)
• Frequent methylation of EBF3 gene is associated with head and neck squamous cell carcinoma (PMID:18559491)
• Findings suggested that the transfection of EBF3 gene into HepG2 induced the cell proliferation from G1 phase to G2 phase by increasing the number of cells. (PMID:18845077)
• Results verify IRX1, EBF3, SLC5A8, SEPT9, and FUSSEL18 as valid methylation markers in two separate sets of HNSCC specimens; also preliminarily show a trend between HPV16 positivity and target gene hypermethylation of IRX1, EBF3, SLC5A8, and SEPT9. (PMID:20029986)
• EBF3 tumor suppressor is epigenetically silenced and that it serves as an independent prognostic marker in gastric carcinoma. (PMID:21387304)
• Early B-cell factor 3 (EBF3) is a novel tumor suppressor gene with promoter hypermethylation in pediatric acute myeloid leukemia (PMID:25609158)
• EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation (PMID:28017370)
• findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations (PMID:28017372)
• findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in approximately 0.1% of individuals with unexplained neurodevelopmental disorders (PMID:28017373)
• Results found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis. (PMID:28030832)
• In 11 affected individuals from 11 unrelated families, we identified de novo variants in EBF3 as potentially causative for the neurodevelopmental phenotype. The variants include one nonsense, two frameshift deletions, one splice, and three missense variants. There are three de novo missense variants, (p.(Lys64Thr), p.(His157Gln), and p.(Arg209Gln), which are all in the COE1 DNA-binding domain. (PMID:29162653)
• Loss of EBF3 expression is associated with Hereditary Melanoma. (PMID:29522175)
• Data show that early B-cell factor 3 (EBF3) was identified as the direct downstream target gene of miR-23b-3p. (PMID:29750239)
• Associations of Pulmonary Fibrosis with Peripheral Blood Th1/Th2 Cell Imbalance and EBF3 Gene Methylation in Uygur Pigeon Breeder’s Lung Patients. (PMID:29913442)
• Findings suggest characteristic DNA methylation changes in EBF3 is relatively common tumor-associated epigenetic events in multiple tumor types, which is consistent with a potential role as more general drivers of tumor progression. (PMID:31383000)
• Clinical spectrum of individuals with de novo EBF3 variants or deletions. (PMID:34050706)
• Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. (PMID:34256850)
• Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype. (PMID:34999443)
• An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain. (PMID:35340043)
• Early B Cell Factor 3 (EBF3) attenuates Parkinson’s disease through directly regulating contactin-associated protein-like 4 (CNTNAP4) transcription: An experimental study. (PMID:38479556)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ebf3a	ENSDARG00000100244
mus_musculus	Ebf3	ENSMUSG00000010476
rattus_norvegicus	Ebf3	ENSRNOG00000016102
drosophila_melanogaster	kn	FBGN0001319
caenorhabditis_elegans		WBGENE00006743

Paralogs (3): EBF4 (ENSG00000088881), EBF1 (ENSG00000164330), EBF2 (ENSG00000221818)

Protein

Protein identifiers

Transcription factor COE3 — Q9H4W6 (reviewed: Q9H4W6)

Alternative names: Early B-cell factor 3, Olf-1/EBF-like 2

All UniProt accessions (2): Q9H4W6, H0Y3W9

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator. Recognizes variations of the palindromic sequence 5’-ATTCCCNNGGGAATT-3'.

Subunit / interactions. Forms either a homodimer or a heterodimer with a related family member.

Subcellular location. Nucleus.

Tissue specificity. Expressed in brain.

Disease relevance. Hypotonia, ataxia, and delayed development syndrome (HADDS) [MIM:617330] An autosomal dominant neurodevelopmental syndrome characterized by global developmental delay, moderate to severe intellectual disability, cerebellar ataxia, hypotonia, speech delay, variable dysmorphic features, and genitourinary abnormalities including vesicoureteric reflux. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the COE family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H4W6-1	Long	yes
Q9H4W6-2	Short

RefSeq proteins (7): NP_001005463, NP_001362308, NP_001362309, NP_001362318, NP_001362319, NP_001362320, NP_001362321 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002909	IPT_dom	Domain
IPR003523	Transcription_factor_COE	Family
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR018350	Transcription_factor_COE_CS	Conserved_site
IPR032200	COE_DBD	Domain
IPR032201	COE_HLH	Domain
IPR038006	COE_IPT	Domain
IPR038173	COE_DBD_sf	Homologous_superfamily

Pfam: PF01833, PF16422, PF16423

UniProt features (35 total): sequence variant 10, strand 10, region of interest 5, helix 3, splice variant 2, site 2, chain 1, domain 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3MUJ	X-RAY DIFFRACTION	1.92
3N50	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4W6-F1	71.89	0.45

Functional residue map

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

Catalytic / active sites (2): 163 (interaction with dna); 172 (interaction with dna)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 482 (showing top): BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, CATTTCA_MIR203, LOPES_METHYLATED_IN_COLON_CANCER_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, TSENG_IRS1_TARGETS_DN, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, TAATGTG_MIR323, CTTTGTA_MIR524, TGCCTTA_MIR124A, ATGTTTC_MIR494, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_CDC25_DN, LEIN_MIDBRAIN_MARKERS, LEIN_PONS_MARKERS, AAGCACA_MIR218

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of DNA-templated transcription (GO:0045893), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
positive regulation of RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transition metal ion binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EBF3	TMTC1	Q8IUR5	661
EBF3	UBE2M	P61081	618
EBF3	DCUN1D1	Q96GG9	571
EBF3	ZNF423	Q2M1K9	557
EBF3	PRDM16	Q9HAZ2	529
EBF3	PAX5	Q02548	513
EBF3	TCF3	P15883	507
EBF3	EHMT1	Q9H9B1	458
EBF3	SETMAR	Q53H47	440
EBF3	IGLL1	P15814	419
EBF3	VPREB1	P12018	419
EBF3	EP300	Q09472	409
EBF3	CREBBP	Q92793	389
EBF3	ZNF521	Q96K83	382
EBF3	UBE2F	Q969M7	380

IntAct

56 interactions, top by confidence:

A	B	Type	Score
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
CPNE2	HIP1	psi-mi:“MI:0914”(association)	0.530
CCL1	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL11	EBF3	psi-mi:“MI:0915”(physical association)	0.370
	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL18	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL22	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL24	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL3	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL3L1	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CCL4L1	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CSF2	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CXCL3	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CXCL5	EBF3	psi-mi:“MI:0915”(physical association)	0.370
CXCL9	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IFNA8	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IFNG	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IFNL4	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IL12B	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IL17A	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IL18	EBF3	psi-mi:“MI:0915”(physical association)	0.370
IL25	EBF3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (29): EBF3 (Affinity Capture-MS), EBF3 (Affinity Capture-MS), EBF3 (Synthetic Lethality), EBF3 (Affinity Capture-MS), EBF3 (Affinity Capture-MS), EBF3 (Affinity Capture-MS), KIAA0430 (Affinity Capture-MS), EBF3 (Affinity Capture-MS), HELZ (Affinity Capture-MS), PAN2 (Affinity Capture-MS), ATPAF2 (Two-hybrid), EBF2 (Two-hybrid), EBF3 (Affinity Capture-MS), EBF3 (Co-purification), EBF3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IWI1, A5ABV9, B7ZRI2, B7ZRJ4, O08791, O08792, O13987, O73673, O73742, O74412, O74954, O93375, P06536, P06537, P49843, P49844, P56721, Q00858, Q03414, Q03571, Q07802, Q08DL5, Q10902, Q13761, Q13950, Q20937, Q23238, Q5H9I0, Q61X54, Q63398, Q64131, Q6E3C9, Q6E3D0, Q6E3D4, Q6E3D5, Q6P4K7, Q6PF39, Q700C2, Q8BYR2, Q8K4J2

Diamond homologs: A0A0R4IWI1, B7ZRI2, B7ZRJ4, O08791, O08792, O73742, O93375, P56721, Q07802, Q08DL5, Q63398, Q6P4K7, Q8K4J2, Q93705, Q9BQW3, Q9H4W6, Q9HAK2, Q9UH73, O13987

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARX	“down-regulates quantity by repression”	EBF3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Interleukin-10 signaling	8	49.1×	3e-10
Chemokine receptors bind chemokines	9	44.3×	5e-11
Interleukin-4 and Interleukin-13 signaling	7	18.9×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
eosinophil chemotaxis	6	91.6×	5e-09
chemokine-mediated signaling pathway	10	67.5×	6e-14
antimicrobial humoral immune response mediated by antimicrobial peptide	10	33.8×	6e-11
positive regulation of interleukin-1 beta production	6	32.4×	1e-06
cell surface receptor signaling pathway via JAK-STAT	5	30.3×	3e-05
neutrophil chemotaxis	5	29.8×	3e-05
humoral immune response	5	29.3×	3e-05
cell chemotaxis	7	27.0×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	49
Uncertain significance	158
Likely benign	53
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032516	NM_001375380.1(EBF3):c.291+2del	Pathogenic
1048549	NM_001375380.1(EBF3):c.622dup (p.Met208fs)	Pathogenic
1048550	GRCh37/hg19 10q26.3(chr10:131542049-132107231)x1	Pathogenic
1068622	NM_001375380.1(EBF3):c.1696del (p.Val566fs)	Pathogenic
1070352	NM_001375380.1(EBF3):c.554+4A>C	Pathogenic
1098317	NM_001375380.1(EBF3):c.291+1G>A	Pathogenic
1179936	NM_001375380.1(EBF3):c.89G>A (p.Trp30Ter)	Pathogenic
1306764	NM_001375380.1(EBF3):c.454C>G (p.Arg152Gly)	Pathogenic
1308632	NM_001375380.1(EBF3):c.239dup (p.Pro81fs)	Pathogenic
1676934	NM_001375380.1(EBF3):c.292-2A>G	Pathogenic
1687681	NM_001375380.1(EBF3):c.587A>G (p.Gln196Arg)	Pathogenic
1699372	NM_001375380.1(EBF3):c.705CAA[1] (p.Asn237del)	Pathogenic
212723	NM_001375380.1(EBF3):c.1128+1G>T	Pathogenic
224085	NM_001375380.1(EBF3):c.530C>T (p.Pro177Leu)	Pathogenic
2265788	NM_001375380.1(EBF3):c.537_544del (p.Pro180fs)	Pathogenic
2429986	NM_001375380.1(EBF3):c.232C>T (p.Gln78Ter)	Pathogenic
2573011	NM_001375380.1(EBF3):c.1346C>G (p.Ser449Ter)	Pathogenic
2577648	NM_001375380.1(EBF3):c.524_528del (p.Glu175fs)	Pathogenic
2637862	NC_000010.10:g.(131676114_131755521)(131762539?)del	Pathogenic
2672420	NM_001375380.1(EBF3):c.237dup (p.Gln80fs)	Pathogenic
268155	NM_001375380.1(EBF3):c.488G>T (p.Arg163Leu)	Pathogenic
268156	NM_001375380.1(EBF3):c.488G>A (p.Arg163Gln)	Pathogenic
3063142	GRCh37/hg19 10q26.2-26.3(chr10:130438796-131875311)x1	Pathogenic
3242598	NM_001375380.1(EBF3):c.347dup (p.Tyr116Ter)	Pathogenic
3391908	GRCh37/hg19 10q26.2-26.3(chr10:130006415-133270077)x1	Pathogenic
374797	NM_001375380.1(EBF3):c.487C>T (p.Arg163Trp)	Pathogenic
375375	NM_001375380.1(EBF3):c.512G>A (p.Gly171Asp)	Pathogenic
375500	NM_001375380.1(EBF3):c.488G>C (p.Arg163Pro)	Pathogenic
375501	NM_001375380.1(EBF3):c.579G>T (p.Lys193Asn)	Pathogenic
375502	NM_001375380.1(EBF3):c.280_283del (p.Glu94fs)	Pathogenic

SpliceAI

3677 predictions. Top by Δscore:

Variant	Effect	Δscore
10:129837956:CATAG:C	acceptor_gain	1.0000
10:129837958:TAG:T	acceptor_gain	1.0000
10:129837961:C:CC	acceptor_gain	1.0000
10:129842111:CATA:C	donor_loss	1.0000
10:129842112:ATAC:A	donor_loss	1.0000
10:129842113:TACC:T	donor_loss	1.0000
10:129842114:ACC:A	donor_loss	1.0000
10:129842298:A:T	acceptor_gain	1.0000
10:129843132:CCTA:C	donor_loss	1.0000
10:129843133:CTA:C	donor_loss	1.0000
10:129843134:TA:T	donor_loss	1.0000
10:129843135:ACCTG:A	donor_loss	1.0000
10:129843200:CTC:C	acceptor_gain	1.0000
10:129843203:C:CC	acceptor_gain	1.0000
10:129873478:CCTT:C	donor_gain	1.0000
10:129873593:CAAC:C	acceptor_gain	1.0000
10:129873597:CTGCA:C	acceptor_loss	1.0000
10:129873598:T:C	acceptor_loss	1.0000
10:129877685:T:TA	donor_gain	1.0000
10:129957323:CCGG:C	acceptor_gain	1.0000
10:129957324:CGGC:C	acceptor_gain	1.0000
10:129958928:GCTCA:G	donor_loss	1.0000
10:129958929:CTCA:C	donor_loss	1.0000
10:129958930:TCACC:T	donor_loss	1.0000
10:129958931:CACCT:C	donor_loss	1.0000
10:129958932:A:T	donor_loss	1.0000
10:129958933:C:A	donor_loss	1.0000
10:129962165:TCTCA:T	donor_loss	1.0000
10:129962166:CTCA:C	donor_loss	1.0000
10:129962167:TCA:T	donor_loss	1.0000

AlphaMissense

4147 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:129840315:G:C	F563L	1.000
10:129840315:G:T	F563L	1.000
10:129840316:A:C	F563C	1.000
10:129840316:A:G	F563S	1.000
10:129840317:A:G	F563L	1.000
10:129840319:G:T	A562D	1.000
10:129843174:A:G	L386P	1.000
10:129843180:G:T	A384E	1.000
10:129843181:C:G	A384P	1.000
10:129843183:G:T	A383E	1.000
10:129843184:C:G	A383P	1.000
10:129843186:C:G	R382P	1.000
10:129843188:C:A	K381N	1.000
10:129843188:C:G	K381N	1.000
10:129843192:A:C	L380R	1.000
10:129843192:A:G	L380P	1.000
10:129843192:A:T	L380Q	1.000
10:129848392:C:A	K376N	1.000
10:129848392:C:G	K376N	1.000
10:129848399:A:G	L374S	1.000
10:129848411:T:C	D370G	1.000
10:129848429:A:T	I364N	1.000
10:129848441:A:C	L360W	1.000
10:129848441:A:G	L360S	1.000
10:129848443:C:A	R359S	1.000
10:129848443:C:G	R359S	1.000
10:129848444:C:A	R359M	1.000
10:129848444:C:G	R359T	1.000
10:129848449:A:C	F357L	1.000
10:129848449:A:T	F357L	1.000

dbSNP variants (sampled 300 via entrez): RS1000014470 (10:129866580 A>C,G), RS1000059800 (10:129883836 ATGG>A), RS1000067253 (10:129900399 G>C), RS1000080397 (10:129895949 A>G), RS1000137633 (10:129854060 T>C), RS1000146593 (10:129921267 T>G), RS1000174127 (10:129896219 T>C), RS1000180816 (10:129940818 G>A), RS1000194390 (10:129933462 G>A), RS1000201086 (10:129858671 A>T), RS1000204256 (10:129894639 G>C), RS1000252520 (10:129854332 C>A,T), RS1000260814 (10:129958921 G>C), RS1000294537 (10:129925075 T>C), RS1000297628 (10:129940140 T>C)

Disease associations

OMIM: gene MIM:607407 | disease phenotypes: MIM:617330, MIM:300958, MIM:157900, MIM:261800

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotonia, ataxia, and delayed development syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypotonia, ataxia, and delayed development syndrome	Definitive	AD

Mondo (10): hypotonia, ataxia, and delayed development syndrome (MONDO:0015021), intellectual disability (MONDO:0001071), autism spectrum disorder (MONDO:0005258), intellectual disability, X-linked 102 (MONDO:0010497), neurodevelopmental disorder (MONDO:0700092), Mobius syndrome (MONDO:0008006), isolated Pierre-Robin syndrome (MONDO:0009869), renal tubular dysgenesis (MONDO:0017609), constipation disorder (MONDO:0002203), vesicoureteral reflux (MONDO:0006007)

Orphanet (7): Developmental delay-ataxia-hypotonia-facial dysmorphism syndrome (Orphanet:658843), X-linked intellectual disability-hypotonia-movement disorder syndrome (Orphanet:457260), Moebius syndrome (Orphanet:570), Isolated Pierre Robin sequence (Orphanet:718), Renal tubular dysgenesis (Orphanet:3033), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

142 total (30 of 142 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000119	Abnormality of the genitourinary system
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000215	Thick upper lip vermilion
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000300	Oval face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000349	Widow’s peak
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002050_4	Sleep time	6.000000e-06
GCST006956_7	Erectile dysfunction	3.000000e-06
GCST009391_1830	Metabolite levels	9.000000e-06
GCST009391_1851	Metabolite levels	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010411	triacylglycerol 50:4 measurement
EFO:0010410	triacylglycerol 50:3 measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003248	Constipation	C23.888.821.150
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595
D065886	Neurodevelopmental Disorders	F03.625
D010855	Pierre Robin Syndrome	C05.500.460.606; C05.660.207.540.460.606; C07.320.440.606; C07.650.500.460.606; C16.131.621.207.540.460.606; C16.131.850.500.460.606
D014718	Vesico-Ureteral Reflux	C12.050.351.968.829.920; C12.200.777.829.920; C12.950.829.920

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
bisphenol A	increases expression, affects methylation, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases methylation	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	affects methylation, decreases methylation	2
bisphenol F	affects cotreatment, increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
MRK 003	increases expression	1
bisphenol S	decreases methylation	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Ascorbic Acid	affects binding, affects cotreatment, increases expression	1
Dexamethasone	increases expression, affects cotreatment	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Hydrocortisone	increases expression, affects cotreatment	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects splicing	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)