EBF3

Chr 10AD

EBF transcription factor 3

Also known as: COE3, EBF-3, HADDS, O/E-2, OE-2

NCBI Gene: 253738ENSG00000108001UniProt: Q9H4W6

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. [provided by RefSeq, Sep 2011]

Primary Disease Associations & Inheritance

Hypotonia, ataxia, and delayed development syndromeMIM #617330
AD
433
ClinVar variants
207
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— EBF3
🧬
Gene-Disease Validity (ClinGen)
hypotonia, ataxia, and delayed development syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
207 Pathogenic / Likely Pathogenic· 156 VUS of 433 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.15LOEUF
pLI 1.000
Z-score 5.05
OE 0.03 (0.01–0.15)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.61Z-score
OE missense 0.46 (0.40–0.52)
163 obs / 354.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.40–0.52)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 1 / 31.7Missense obs/exp: 163 / 354.3Syn Z: 0.50

ClinVar Variant Classifications

433 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic150
Likely Pathogenic57
VUS156
Likely Benign57
Benign8
Conflicting5
150
Pathogenic
57
Likely Pathogenic
156
VUS
57
Likely Benign
8
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
24
14
112
0
150
Likely Pathogenic
13
34
10
0
57
VUS
8
115
30
3
156
Likely Benign
0
11
11
35
57
Benign
0
0
5
3
8
Conflicting
—5
Total4517416841433

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

EBF3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

EBF3-related intellectual disability, ataxia, and facial dysmorphism

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hypotonia, ataxia, and delayed development syndrome

MIM #617330

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — EBF3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical spectrum of individuals with de novo EBF3 variants or deletions.
Nishi E et al.·Am J Med Genet A
2021
Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype.
Ignatius E et al.·Eur J Paediatr Neurol
2022
An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain.
Deisseroth CA et al.·Ann Neurol
2022Meta-analysis
A nonsense variant in the C-terminal transactivation domain of the EBF3 gene in an individual with intellectual disability and behavioural disorder: case report and literature review.
Spineli-Silva S et al.·Psychiatr Genet
2025Review
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.
Lee AS et al.·Nat Commun
2024
The natural history of progressive myoclonus ataxia.
van der Veen S et al.·Neurobiol Dis
2024Natural history
Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.
Harms FL et al.·Am J Hum Genet
2017
Whole Genome Sequencing of "Mutation-Negative" Individuals With Cornelia de Lange Syndrome.
Ansari M et al.·Hum Mutat
2025
Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.
Padhi EM et al.·Hum Genomics
2021
SNORA47 affects stemness and chemotherapy sensitivity via EBF3/RPL11/c-Myc axis in luminal A breast cancer.
Han Q et al.·Mol Med
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools