SEMA4A
protein-codingsemaphorin 4A, the group of Semaphorins
Gene summary
This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]
- SEMAB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0012464
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0012463
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019118
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018604
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015993
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: ClinGen
*SEMA4* encodes Semaphorin 4A, a single-pass type I membrane protein involved in axon guidance, morphogenesis, carcinogenesis, and immunomodulation. Although there is no disease associated with SEMA4 in OMIM, there was an early assertion of association with Lynch syndrome (Schulz et al. PMID: 25307848). This curation will focus on this disorder. In 2014, Schulz and co-workers first proposed the association of germline SEMA4 variants in autosomal dominant Lynch syndrome by reporting a missense variant (splice site and missense) in a family with Lynch syndrome. This study also found that this variant is associated with colorectal cancer by a case-control analysis. However, in 2016, Kinnersley et al reported a well-powered study showing no statistical significance between this variant and colorectal cancer. The pedigree from the family with colorectal cancer also showed incomplete segregation. Hence Kinnersley et al concluded that there is an issue of type 1 error in Schulz et al. paper. Considering the lack of substantial association in genetic and experimental studies, the Hereditary Cancer GCEP has disputed this gene-disease association. More evidence is needed to either support or entirely refute the role SEMA4A plays in autosomal dominant Lynch syndrome. This gene-disease pair was originally evaluated as limited by the Colon Cancer GCEP on 11/13/2017. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 3/22/2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0012463
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SEMA4A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022367.4. 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 | 5 | 150 | 155 | |||
| missense | 1 | 2 | 372 | 23 | 2 | 400 |
| nonsense | 1 | 1 | 9 | 11 | ||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 4 | 16 | 21 | ||
| splice donor/acceptor (+/-2bp) | 4 | 8 | 12 | |||
| Total | 3 | 12 | 410 | 173 | 2 | 600 |
Highest pathogenic variant AF is 0.000016731423
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071762.2 | 14 | MANE Select | |
| Ensembl | ENSP00000357268.3 | 14 | MANE Select | |
| RefSeq | NP_001180229.1 | 14 | Standard | |
| RefSeq | NP_001180230.1 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sema4aa | Danio rerio | Structure: retinal outer plexiform layer Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Axon guidance - Homo sapiens (human)
- Angiogenesis overview
- Developmental Biology
- Other semaphorin interactions
- Semaphorin interactions
Biological Process
- angiogenesis
- neural crest cell migration
- axonogenesis
- regulation of cell shape
- regulation of endothelial cell migration
Molecular Function
- protein binding
- semaphorin receptor binding
- neuropilin binding
- chemorepellent activity
Cellular Component
- extracellular space
- nucleus
- cytosol
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000368285
- Coding exons
- 14
- Length
- 30387
- Individuals with no LoFs
- 125683
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125748
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.223 | 412 | 425 | 0.970 | 0.0000245 | 4921 |
| Missense (PolyPhen) | 111 | 130.64 | 0.84967 | 1603 | ||
| Synonymous | 0.388 | 173 | 180 | 0.963 | 0.0000102 | 1595 |
| Loss of Function | 3.19 | 14 | 34.1 | 0.410 | 0.00000185 | 373 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00020 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00053 | 0.00052 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Cell surface receptor for PLXNB1, PLXNB2, PLXNB3 and PLXND1 that plays an important role in cell-cell signaling. Plays a role in priming antigen-specific T-cells, promotes differentiation of Th1 T-helper cells, and thereby contributes to adaptive immunity. Promotes phosphorylation of TIMD2. Inhibits angiogenesis. Promotes axon growth cone collapse. Inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons (By similarity). {ECO:0000250|UniProtKB:Q62178}.;
- Disease
- DISEASE: Retinitis pigmentosa 35 (RP35) [MIM:610282]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:16199541, ECO:0000269|PubMed:22956603}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cone-rod dystrophy 10 (CORD10) [MIM:610283]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:16199541}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.127
Intolerance Scores
- LoFtool
- 0.895
- RVIS EVS
- 0.02
- RVIS percentile EVS
- 55.76
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.739
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |