Human Gene Module / Chromosome 5 / SEMA5A

SEMA5Asema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
14 / 20
Rare Variants / Common Variants
14 / 2
Aliases
SEMA5A, Semaphorin 5A,  semF,  SEMAF
Associated Syndromes
-
Chromosome Band
5p15.31
Associated Disorders
ID
Relevance to Autism

Expression of the SEMA5A gene has been shown to be down-regulated in some autistic individuals (Melin et al., 2006).

Molecular Function

The encoded protein is a member of the semaphorin family of membrane proteins that play roles in axonal guidance during neural development.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SEMA5A (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Plexin-B3 is a functional receptor for semaphorin 5A Artigiani S , et al. (2004) No -
2 Recent Recommendation Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans Kantor DB , et al. (2004) No -
3 Highly Cited Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system Fiore R , et al. (2005) No -
4 Primary Constitutional downregulation of SEMA5A expression in autism Melin M , et al. (2006) Yes -
5 Positive Association A genome-wide linkage and association scan reveals novel loci for autism Weiss LA , et al. (2009) Yes -
6 Negative Association The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families Prandini P , et al. (2012) Yes -
7 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
8 Recent Recommendation An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk Cheng Y , et al. (2013) No -
9 Recent Recommendation The SEMA5A gene is associated with hippocampal volume, and their interaction is associated with performance on Raven's Progressive Matrices Zhu B , et al. (2013) No -
10 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
11 Recent Recommendation Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells Duan Y , et al. (2014) No -
12 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
13 Support A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability Mosca-Boidron AL , et al. (2015) Yes ID
14 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms D'Gama AM , et al. (2015) Yes -
15 Negative Association Lack of replication of previous autism spectrum disorder GWAS hits in European populations Torrico B , et al. (2016) Yes -
16 Positive Association Polymorphism in the Promoter Region of SEMA5A Is Associated with Sociality Traits in Korean Subjects with Autism Spectrum Disorders Kim SA , et al. (2017) Yes Sociability traits (as measured by SRS)
17 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
18 Support - Zhou X et al. (2022) Yes -
19 Support - Hu C et al. (2023) Yes -
20 Support - et al. () Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss De novo - Simplex 26395558 Mosca-Boidron AL , et al. (2015)
c.1361G>C p.Arg454Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2872G>A p.Val958Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3106-5dup - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.586C>T p.Arg196Ter stop_gained Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2026C>T p.Arg676Cys missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.2103T>A p.Cys701Ter stop_gained De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.246G>T p.Gln82His missense_variant Unknown Not tested - 24690944 Brett M , et al. (2014)
c.2271C>T p.Ser757%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2852C>G p.Ser951Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2866A>G p.Ser956Gly missense_variant Unknown - Unknown 26395558 Mosca-Boidron AL , et al. (2015)
c.2026C>T p.Arg676Cys missense_variant Familial Maternal Simplex 26395558 Mosca-Boidron AL , et al. (2015)
c.2983C>T p.Arg995Trp missense_variant Familial Maternal Simplex 26395558 Mosca-Boidron AL , et al. (2015)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 29209394 Kim SA , et al. (2017)
- - intergenic_variant - - - 19812673 Weiss LA , et al. (2009)
SFARI Gene score
2

Strong Candidate

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[Lack of replication of previous autism spectrum disorder GWAS hits in European populations.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[Constitutional downregulation of SEMA5A expression in autism.2006] [A genome-wide linkage and association scan reveals novel loci for autism.2009] [The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.2012] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Plexin-B3 is a functional receptor for semaphorin 5A.2004] [Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans.2004] [Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system.2005] [An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk.2013] [The SEMA5A gene is associated with hippocampal volume, and their interaction is associated with performance on Raven's Progressive Matrices.2013] [Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.2014] [A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability.2015] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]
10/1/2014
3
icon
3

Decreased from 3 to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.2014]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

A common variant located in the EST DB512398, located between SEMA5A and TAS2R1, was found to be associated with autism (P = 1.7 x 10-7 considering discovery and replication cohorts). The weak block structure in the region doesn?t seem to permit simple assignment of rs10513025 to SEMA5A (perhaps neighboring SNPs are better in this regard). Neither EST nor SNORD123, each closer to the SNP in question than SEMA5A, were really discussed as possible candidates. Significantly different expression levels for SEMA5A were observed in occipital cortex of ASD cases and controls (Melin M et al.).

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014]
Krishnan Probability Score

Score 0.53056394384165

Ranking 1546/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.0009795943226773

Ranking 11799/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94382568694961

Ranking 15837/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 12

Ranking 163/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.33055474455293

Ranking 2287/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
PLXNB3 plexin B3 Human Protein Binding 5365 Q9ULL4
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