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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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

41 unique Pathogenic / Likely Pathogenic· 52 VUS of 100 total submissions

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Clinical Trials

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

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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 OE0.03 (0.01–0.15)

0≤0.351.4

Missense OE0.46 (0.40–0.52)

0≤0.61.4

Synonymous OE0.95

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

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 · 24% of P/LP variants are LoF · LOEUF 0.15

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.PMID:28017373

LOFWhole Gene Deletion of EBF3 Supporting Haploinsufficiency of This Gene as a Mechanism of Neurodevelopmental DiseasePMID:29062322

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