EBF3

Chr 10AD

EBF transcription factor 3

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

NCBI Gene: 253738 ENSG00000108001 UniProt: Q9H4W6 OMIM: 607407

EBF3 encodes a transcriptional activator that recognizes specific palindromic DNA sequences and is involved in B-cell differentiation, bone development, and neurogenesis. Mutations cause hypotonia, ataxia, and delayed development syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.15), reflecting its critical role in normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

Clinical Summary— EBF3

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Gene-Disease Validity (ClinGen)

hypotonia, ataxia, and delayed development syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

116 unique Pathogenic / Likely Pathogenic· 155 VUS of 354 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EBF3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.03 (0.01–0.15)

0≤0.351.4

Missense OE?0.46 (0.40–0.52)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 31.7Missense obs/exp: 163 / 354.3Syn Z: 0.50

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveEBF3-related intellectual disability, ataxia, and facial dysmorphismLOFAD

This gene — mechanism propensity

0.3991th %ile

GOF

0.3293th %ile

LOF

0.85top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 52% of P/LP variants are LoF · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNIn contrast, co-expression of EBF3WT and each of the mutants p.Asn66Asp, p.Tyr141Cys, p.His157_Ile159dup, p.Arg303?, and p.Gln305? caused a significant reduction in reporter activity by 40%50% (Figure S4), suggesting a potential dominant-negative impact of these variants on the wild-type allele.1

LOFWhole Gene Deletion of EBF3 Supporting Haploinsufficiency of This Gene as a Mechanism of Neurodevelopmental Disease2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59

Likely Pathogenic57

VUS155

Likely Benign59

Benign8

Conflicting5

Pathogenic

Likely Pathogenic

155

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	41	16	2	0	59
Likely Pathogenic	19	36	2	0	57
VUS	9	125	18	3	155
Likely Benign	0	11	12	36	59
Benign	0	0	5	3	8
Conflicting	—				5
Total	69	188	39	42	343

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

View in ClinVar →

98 pathogenic / likely-pathogenic (of 107) ClinVar copy-number / structural variants overlap EBF3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →