SEMA3E
protein-codingsemaphorin 3E, the group of Immunoglobulin like domain containing|Semaphorins
Gene summary
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]
- SEMAH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~285.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:1010178
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008965
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018800
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0008965
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008965
Submitter: ClinGen
The SEMA3E gene was first associated with autosomal dominant CHARGE syndrome in 2004 (PMID: 15235037), but the associated, presumed de novo variant p.Ser703Leu was later reclassified as a variant of unknown significance (PMID: 32441320, Hamosh (2022)). A subsequent report further links another SEMA3E variant to a fetus from terminated pregnancy with ultrasound consistent with the CHARGE syndrome (PMID: 31691538). Heterozygous SEMA3E variants exhibit a broad phenotypic spectrum, including intellectual disability and Kallmann syndrome characterized by hypogonadotropic hypogonadism (PMID: 25985275, 38593951, 35628442). Although immunodeficiency is a recognized feature in other genetic causes of CHARGE syndrome (driven by abnormal thymic development and T-cell lymphopenia), clinical manifestations of immunodeficiency were only linked to a presumed de novo SEMA3E variant in one genetic screening study of an IEI cohort report describing twins with an inborn error of immunity phenotype but none of the typical CHARGE syndrome features, and detailed immunophenotyping was not performed (PMID: 32441320). Mechanistically, zebrafish knockdown studies demonstrate typical CHARGE-like non-immunological phenotypes that can be rescued by SEMA3E overexpression (PMID: 31464029). In summary, there is limited evidence to support this gene-disease relationship. This classification was approved by the ClinGen SCID-CID Working Group on 8/20/2026 (SOP Version 12).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SEMA3E variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012431.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 184 | 3 | 194 | ||
| missense | 3 | 468 | 20 | 1 | 492 | |
| nonsense | 13 | 13 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 10 | 12 | |||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 0 | 5 | 506 | 204 | 4 | 719 |
Highest pathogenic variant AF is 0.000016728354
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036563.1 | 17 | MANE Select | |
| Ensembl | ENSP00000496491.1 | 17 | MANE Select | |
| RefSeq | NP_001171600.1 | 16 | Standard | |
| Ensembl | ENSP00000415184.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sema3e | Danio rerio | Structure: axial vasculature Quality: has fewer parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Axon guidance - Homo sapiens (human)
- Developmental Biology
- Other semaphorin interactions
- Semaphorin interactions
- Plexin-D1 Signaling
Biological Process
- branching involved in blood vessel morphogenesis
- neural crest cell migration
- negative regulation of cell-matrix adhesion
- sprouting angiogenesis
- regulation of cell shape
Molecular Function
- protein binding
- semaphorin receptor binding
- neuropilin binding
- chemorepellent activity
Cellular Component
- extracellular region
- extracellular space
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000307792
- Coding exons
- 17
- Length
- 285105
- Individuals with no LoFs
- 125713
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 35
- Defined
- 125748
- p
- 0.000139
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.465 | 408 | 435 | 0.937 | 0.0000235 | 5096 |
| Missense (PolyPhen) | 137 | 172.08 | 0.79612 | 2018 | ||
| Synonymous | -2.28 | 189 | 153 | 1.23 | 0.00000844 | 1426 |
| Loss of Function | 3.27 | 21 | 44.5 | 0.472 | 0.00000252 | 519 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00032 | 0.00032 | rare |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in signaling via the cell surface receptor PLXND1. Mediates reorganization of the actin cytoskeleton, leading to the retraction of cell projections. Promotes focal adhesion disassembly and inhibits adhesion of endothelial cells to the extracellular matrix. Regulates angiogenesis, both during embryogenesis and after birth. Can down- regulate sprouting angiogenesis. Required for normal vascular patterning during embryogenesis. Plays an important role in ensuring the specificity of synapse formation (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.112
Intolerance Scores
- LoFtool
- 0.718
- RVIS EVS
- -0.8
- RVIS percentile EVS
- 12.49
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.158
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |