SEMA3A

semaphorin 3A, the group of Immunoglobulin like domain containing|Semaphorins

Basic information

Region (hg38): 7:83955776-84492724

Previous symbols: [ "SEMAD" ]

Links

ENSG00000075213 ∙ NCBI:10371 ∙ OMIM:603961 ∙ HGNC:10723 ∙ Uniprot:Q14563 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kallmann syndrome (Supportive), mode of inheritance: AD
• Brugada syndrome (Supportive), mode of inheritance: AD
• hypogonadotropic hypogonadism 16 with or without anosmia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypogonadotropic hypogonadism 16 with or without anosmia	AD	Endocrine	Surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease; In order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required	Endocrine; Genitourinary; Neurologic	22416012
Surveillance in adolescence related to sexual maturation is indicated, and in order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SEMA3A gene.

• not provided (128 variants)
• SEMA3A-related condition (24 variants)
• Inborn genetic diseases (18 variants)
• not specified (7 variants)
• Hypogonadotropic hypogonadism 16 with or without anosmia (7 variants)
• Martsolf syndrome 1 (1 variants)
• Delayed puberty (1 variants)
• Amenorrhea (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SEMA3A 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				20	5	25
missense			53	6	1	60
nonsense		1	1			2
start loss						0
frameshift						0
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1	2	3	6
non coding				12	47	59
Total	0	1	55	38	53

Variants in SEMA3A

This is a list of pathogenic ClinVar variants found in the SEMA3A region.

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

Position	Type	Phenotype	Significance	ClinVar
7-83961370-C-T		SEMA3A-related disorder	Likely benign (Apr 19, 2022)
7-83961401-G-A		SEMA3A-related disorder	Likely benign (Jan 13, 2023)
7-83961420-C-T		SEMA3A-related disorder	Uncertain significance (Dec 18, 2023)
7-83961430-T-G			Uncertain significance (Sep 06, 2022)
7-83961449-T-C			Likely benign (Jun 06, 2018)
7-83961457-T-C		Inborn genetic diseases • SEMA3A-related disorder	Uncertain significance (Jun 20, 2023)
7-83961487-G-A		SEMA3A-related disorder	Uncertain significance (Jan 02, 2024)
7-83961489-C-T		Hypogonadotropic hypogonadism 16 with or without anosmia • SEMA3A-related disorder	Uncertain significance (Dec 31, 2023)
7-83961498-C-T		Martsolf syndrome 1	Uncertain significance (Apr 01, 2022)
7-83961527-C-T		SEMA3A-related disorder	Likely benign (Dec 16, 2021)
7-83961536-T-C		not specified	Benign (Jan 31, 2024)
7-83961536-TG-CA		SEMA3A-related disorder	Conflicting classifications of pathogenicity (Aug 10, 2023)
7-83961537-G-A		Delayed puberty • SEMA3A-related disorder	Conflicting classifications of pathogenicity (Feb 23, 2022)
7-83961547-T-G		Inborn genetic diseases	Uncertain significance (Aug 28, 2023)
7-83961555-T-C		Inborn genetic diseases	Uncertain significance (Feb 28, 2023)
7-83961606-C-T		Inborn genetic diseases	Uncertain significance (Jan 19, 2022)
7-83961625-T-C		Hypogonadotropic hypogonadism 16 with or without anosmia • SEMA3A-related disorder	Uncertain significance (Feb 21, 2024)
7-83961641-A-G			Likely benign (Apr 07, 2018)
7-83961657-A-T			Uncertain significance (Aug 17, 2023)
7-83961667-C-T			Uncertain significance (Nov 01, 2022)
7-83961683-A-AATG		SEMA3A-related disorder	Uncertain significance (Apr 11, 2023)
7-83961727-G-A		Inborn genetic diseases	Uncertain significance (Jun 02, 2023)
7-83961733-C-T		Inborn genetic diseases • SEMA3A-related disorder	Conflicting classifications of pathogenicity (Feb 05, 2024)
7-83961734-C-T		not specified • SEMA3A-related disorder	Benign/Likely benign (Apr 10, 2023)
7-83961735-G-T			Uncertain significance (Jul 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SEMA3A	protein_coding	protein_coding	ENST00000265362	17	536948

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.978	0.0221	125732	0	15	125747	0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.75	327	429	0.762	0.0000225	5118
Missense in Polyphen		120	187.72	0.63924		2215
Synonymous	0.510	143	151	0.947	0.00000810	1400
Loss of Function	5.27	8	47.0	0.170	0.00000287	499

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000124	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.000114	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000888	0.0000879
Middle Eastern	0.000114	0.000109
South Asian	0.0000329	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1. {ECO:0000269|PubMed:22416012}.
• Disease: DISEASE: Hypogonadotropic hypogonadism 16 with or without anosmia (HH16) [MIM:614897]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:22416012, ECO:0000269|PubMed:22927827, ECO:0000269|PubMed:25077900}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.
• Pathway: Axon guidance - Homo sapiens (human);Angiogenesis overview;Olfactory bulb development and olfactory learning;Developmental Biology;SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion;Sema3A PAK dependent Axon repulsion;Semaphorin interactions;Axon guidance;CRMPs in Sema3A signaling (Consensus)

Recessive Scores

• pRec: 0.414

Intolerance Scores

• loftool: 0.477
• rvis_EVS: 0.34
• rvis_percentile_EVS: 73.68

Haploinsufficiency Scores

• pHI: 0.848
• hipred: Y
• hipred_score: 0.704
• ghis: 0.453

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.473

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sema3a
• Phenotype: hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; skeleton 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); growth/size/body region phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: sema3ab
• Affected structure: intersegmental vessel
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: neural crest cell migration;neuron migration;regulation of heart rate;apoptotic process;axon guidance;axonal fasciculation;negative regulation of epithelial cell migration;negative regulation of neuron projection development;facial nerve structural organization;trigeminal nerve structural organization;nerve development;olfactory bulb development;branchiomotor neuron axon guidance;gonadotrophin-releasing hormone neuronal migration to the hypothalamus;positive regulation of cell migration;ventral trunk neural crest cell migration;positive regulation of JNK cascade;sympathetic nervous system development;regulation of axon extension involved in axon guidance;negative regulation of axon extension involved in axon guidance;axon extension involved in axon guidance;sensory system development;negative chemotaxis;axonogenesis involved in innervation;dichotomous subdivision of terminal units involved in salivary gland branching;sympathetic ganglion development;trigeminal ganglion development;semaphorin-plexin signaling pathway;sympathetic neuron projection extension;sympathetic neuron projection guidance;basal dendrite arborization;neural crest cell migration involved in autonomic nervous system development;semaphorin-plexin signaling pathway involved in neuron projection guidance;semaphorin-plexin signaling pathway involved in axon guidance;neural crest cell migration involved in sympathetic nervous system development;facioacoustic ganglion development;positive regulation of male gonad development;positive regulation of neuron migration
• Cellular component: extracellular region;extracellular space;integral component of plasma membrane;axon;dendrite
• Molecular function: semaphorin receptor binding;neuropilin binding;chemorepellent activity