SEMA3E

Chr 7

semaphorin 3E

Also known as: M-SEMAH, M-SemaK, SEMAH, coll-5

NCBI Gene: 9723 ENSG00000170381 UniProt: O15041

Semaphorin 3E is a secreted axon guidance protein that signals through the PLXND1 receptor to regulate actin cytoskeleton reorganization, vascular patterning during development, and synaptic specificity. Mutations cause CHARGE syndrome, a multisystem disorder affecting the heart, eyes, ears, genitals, and nervous system with features typically apparent at birth. SEMA3E follows autosomal dominant inheritance and is intolerant to loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, UniProt

Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

GeneReviews ResearchGenerating clinical summary…

DNmechanismLOEUF 0.68

Clinical Summary— SEMA3E

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 465 VUS of 910 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SEMA3E

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.68LOEUF

pLI 0.000

Z-score 3.27

OE 0.47 (0.33–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.46Z-score

OE missense 0.94 (0.86–1.02)

408 obs / 435.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.33–0.68)

0≤0.351.4

Missense OE?0.94 (0.86–1.02)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 21 / 44.5Missense obs/exp: 408 / 435.3Syn Z: -2.28

This gene — mechanism propensity

0.6938th %ile

GOF

0.5955th %ile

LOF

0.2970th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

910 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS465

Likely Benign318

Benign104

Conflicting14

Likely Pathogenic

465

VUS

318

Likely Benign

104

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	0	0	0	2
VUS	27	408	23	7	465
Likely Benign	0	7	142	169	318
Benign	0	2	97	5	104
Conflicting	—				14
Total	29	417	262	181	903

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap SEMA3E — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →