EFNB3

Chr 17

ephrin B3

Also known as: EFL6, EPLG8, LERK8

NCBI Gene: 1949 ENSG00000108947 UniProt: Q15768 OMIM: 602297

The EFNB3 protein functions as a cell surface ligand for Eph receptors that mediates bidirectional signaling crucial for neuronal migration, axon guidance, and forebrain development, particularly in constraining axon orientation and inducing growth cone collapse. Mutations cause autosomal dominant intellectual disability with craniofacial dysmorphism and seizures, typically presenting in early childhood. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.607), consistent with its role in neurodevelopment.

OMIM ResearchSummary from UniProt

EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. Moreover, since levels of EFNB3 expression were particularly high in several forebrain subregions compared to other brain subregions, it may play a pivotal role in forebrain function. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. EPH Receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997). Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are similarly divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.61

Clinical Summary— EFNB3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 38 VUS of 45 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.320

Z-score 2.54

OE 0.23 (0.11–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.57Z-score

OE missense 0.69 (0.59–0.79)

136 obs / 198.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.11–0.61)

0≤0.351.4

Missense OE?0.69 (0.59–0.79)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 12.8Missense obs/exp: 136 / 198.4Syn Z: -0.68

This gene — mechanism propensity

0.6161th %ile

GOF

0.72top 25%

LOF

0.4726th %ile

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

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

45 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS38

Benign1

Pathogenic

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	1	1
Likely Pathogenic	0	0	0
VUS	38	0	38
Likely Benign	0	0	0
Benign	1	0	1
Total	39	1	40

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap EFNB3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →