GeneBe

SEMA3A

protein-coding

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

Gene summary

This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]

Previous symbols:
  • SEMAD

MANE transcript

NM_006080.3

Inheritance

AD, SD, AR

ClinVar variants

P:8U:257B:107

Top phenotype

Hypogonadotropic hypogonadism 16 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr7:83,955,777-84,492,724

External References & Databases

Ensembl (ENSG00000075213)NCBI Gene (10371)OMIM (603961)HGNC:10723GenCCUniProt (Q14563)AlphaFoldClinVar (SEMA3A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~536.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 16 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013961

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 16 with or without anosmiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0013961

Submitter: PanelApp Australia

skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018230

Submitter: G2P

Kallmann syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018800

Submitter: Orphanet

Brugada syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Orphanet

multiple congenital anomalies/dysmorphic syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

hypogonadotropic hypogonadism 16 with or without anosmiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013961

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 16 with or without anosmiaAD

Manifestation: Endocrine; Genitourinary; Neurologic

Intervention: Endocrine

Rationale: 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

Comments: 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

Refs: 22416012Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SEMA3A variants in ClinVar

11 Conditions Cataloged
SEMA3A-related disorderTotal: 306
not providedTotal: 136
Inborn genetic diseasesTotal: 83
not specifiedTotal: 25
Hypogonadotropic hypogonadism 16 with or without anosmiaTotal: 19
Male infertility with azoospermia or oligozoospermia due to single gene mutationTotal: 1
Delayed pubertyTotal: 1
AmenorrheaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006080.3. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
86
clinvar
3
clinvar
 93
missense
1
clinvar
242
clinvar
18
clinvar
 261
nonsense
3
clinvar
4
clinvar
 7
start loss
0
frameshift
2
clinvar
3
clinvar
 5
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
4
clinvar
 6
Total172571043372

Highest pathogenic variant AF is 0.000141143

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006080.3RefSeqNP_006071.117MANE Select
ENST00000265362.9EnsemblENSP00000265362.317MANE Select
ENST00000420047.1EnsemblENSP00000391900.14Standard
ENST00000424555.5EnsemblENSP00000404800.11Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
sema3abDanio rerio

Structure: intersegmental vessel

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
  • Olfactory bulb development and olfactory learning
  • Developmental Biology
  • SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion

Biological Process

  • neural crest cell migration
  • neuron migration
  • regulation of heart rate
  • apoptotic process
  • axon guidance

Molecular Function

  • semaphorin receptor binding
  • neuropilin binding
  • chemorepellent activity

Cellular Component

  • extracellular region
  • extracellular space
  • integral component of plasma membrane
  • axon
  • dendrite

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000265362
Coding exons
17
Length
536948
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
15
Defined
125747
p
0.0000596
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.753274290.7620.00002255118
Missense (PolyPhen)120187.720.639242215
Synonymous0.5101431510.9470.000008101400
Loss of Function5.27847.00.1700.00000287499

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.0000890.000088rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.414

Intolerance Scores

LoFtool
0.477
RVIS EVS
0.34
RVIS percentile EVS
73.68

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.473

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.