SEMA4A

semaphorin 4A, the group of Semaphorins

Basic information

Region (hg38): 1:156147365-156177752

Previous symbols: [ "SEMAB" ]

Links

ENSG00000196189 ∙ NCBI:64218 ∙ OMIM:607292 ∙ HGNC:10729 ∙ Uniprot:Q9H3S1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• retinitis pigmentosa (Supportive), mode of inheritance: AD
• cone-rod dystrophy (Supportive), mode of inheritance: AD
• familial colorectal cancer type X (Supportive), mode of inheritance: AD
• retinitis pigmentosa 35 (Limited), mode of inheritance: AR
• cone-rod dystrophy 10 (Limited), mode of inheritance: Unknown
• retinitis pigmentosa 35 (Limited), mode of inheritance: Unknown
• Lynch syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cone-rod dystrophy 10; Retinitis pigmentosa 35	AR	General	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	Ophthalmologic	16199541

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SEMA4A gene.

• not provided (468 variants)
• Cone-rod dystrophy 10 (83 variants)
• Retinitis pigmentosa (60 variants)
• Retinitis pigmentosa 35 (41 variants)
• Retinitis Pigmentosa, Recessive (36 variants)
• Inborn genetic diseases (23 variants)
• not specified (9 variants)
• Retinal dystrophy (4 variants)
• Cone-rod dystrophy 10;Retinitis pigmentosa 35 (3 variants)
• Colorectal cancer (2 variants)
• Cone-Rod Dystrophy, Recessive (2 variants)
• Polyp of colon (1 variants)
• Helicoid peripapillary chorioretinal degeneration (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SEMA4A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	87	1	93
missense			253	6		259
nonsense	1		8			9
start loss			1			1
frameshift	1	2	9			12
inframe indel			7			7
splice donor/acceptor (+/-2bp)			6		1	7
splice region			4	15		19
non coding			19	47	6	72
Total	2	2	308	140	8

Highest pathogenic variant AF is 0.0000131

Variants in SEMA4A

This is a list of pathogenic ClinVar variants found in the SEMA4A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-156153519-C-T		Cone-Rod Dystrophy, Recessive • Retinitis Pigmentosa, Recessive	Uncertain significance (Jun 14, 2016)
1-156153629-G-A		Cone-rod dystrophy 10 • Retinitis Pigmentosa, Recessive • Retinitis pigmentosa	Uncertain significance (Jan 13, 2018)
1-156153730-A-G		Cone-rod dystrophy 10 • Retinitis Pigmentosa, Recessive • Retinitis pigmentosa	Uncertain significance (Jan 13, 2018)
1-156154580-T-A			Uncertain significance (Mar 20, 2022)
1-156154589-C-T			Uncertain significance (Jun 14, 2023)
1-156154592-C-G			Uncertain significance (Dec 28, 2020)
1-156154598-G-A		Retinitis pigmentosa • Cone-rod dystrophy 10	Conflicting classifications of pathogenicity (Jan 25, 2024)
1-156154612-A-T			Uncertain significance (Apr 05, 2021)
1-156154616-T-C		not specified	Uncertain significance (Oct 05, 2023)
1-156154621-G-T			Uncertain significance (Sep 23, 2022)
1-156154623-C-T			Likely benign (Nov 23, 2021)
1-156154639-C-T			Likely benign (Mar 26, 2022)
1-156154654-C-A			Uncertain significance (May 19, 2021)
1-156154655-T-C			Uncertain significance (Sep 27, 2022)
1-156154655-T-TGCC			Uncertain significance (Aug 16, 2022)
1-156154657-C-T			Uncertain significance (Oct 14, 2022)
1-156154657-CCGA-C			Uncertain significance (Nov 10, 2023)
1-156154658-C-T			Uncertain significance (Nov 12, 2023)
1-156154659-G-A		SEMA4A-related disorder	Likely benign (Jan 21, 2020)
1-156154661-C-T			Uncertain significance (Aug 08, 2022)
1-156154662-G-A		not specified • Retinitis Pigmentosa, Recessive • Cone-rod dystrophy 10 • Retinitis pigmentosa	Conflicting classifications of pathogenicity (Dec 13, 2023)
1-156154662-G-GA			Uncertain significance (Feb 24, 2023)
1-156154664-C-T		Cone-rod dystrophy 10 • Retinitis pigmentosa 35 • not specified	Uncertain significance (Apr 11, 2023)
1-156154665-G-A			Likely benign (Sep 27, 2022)
1-156154667-C-A			Uncertain significance (Mar 20, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SEMA4A	protein_coding	protein_coding	ENST00000368285	14	30387

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000184	1.00	125683	0	65	125748	0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.223	412	425	0.970	0.0000245	4921
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000535	0.000535
Ashkenazi Jewish	0.000298	0.000198
East Asian	0.000272	0.000272
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000230	0.000229
Middle Eastern	0.000272	0.000272
South Asian	0.000525	0.000523
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Axon guidance - Homo sapiens (human);Angiogenesis overview;Developmental Biology;Other semaphorin interactions;Semaphorin interactions;Plexin-D1 Signaling;Axon guidance (Consensus)

Recessive Scores

• pRec: 0.127

Intolerance Scores

• loftool: 0.895
• rvis_EVS: 0.02
• rvis_percentile_EVS: 55.76

Haploinsufficiency Scores

• pHI: 0.768
• hipred: Y
• hipred_score: 0.655
• ghis: 0.519

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.739

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Sema4a
• Phenotype: cellular phenotype; immune system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); pigmentation phenotype; hematopoietic system phenotype

Zebrafish Information Network

• Gene name: sema4aa
• Affected structure: retinal outer plexiform layer
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: angiogenesis;neural crest cell migration;axonogenesis;regulation of cell shape;regulation of endothelial cell migration;negative regulation of angiogenesis;positive regulation of cell migration;T-helper 1 cell differentiation;negative regulation of axon extension involved in axon guidance;negative chemotaxis;semaphorin-plexin signaling pathway
• Cellular component: extracellular space;nucleus;cytosol;plasma membrane;integral component of plasma membrane;intracellular membrane-bounded organelle
• Molecular function: protein binding;semaphorin receptor binding;neuropilin binding;chemorepellent activity