Human Gene Module / Chromosome X / PLXNA3

PLXNA3plexin A3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
26 / 0
Aliases
PLXNA3, 6.3,  HSSEXGENE,  PLXN3,  PLXN4,  XAP-6
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
ASD
Relevance to Autism

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567. Steele et al., 2021 reported 14 males with maternally-inherited hemizygous PLXNA3 variants; all 14 individuals presented with intellectual disability, and 13 of these individuals also presented with autism spectrum disorder.

Molecular Function

This gene encodes a member of the plexin class of proteins. The encoded protein is a class 3 semaphorin receptor, and may be involved in cytoskeletal remodeling and as well as apoptosis. Studies of a similar gene in zebrafish suggest that it is important for axon pathfinding in the developing nervous system.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PLXNA3 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
2 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
3 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Autistic features
4 Support Genetic landscape of autism spectrum disorder in Vietnamese children Tran KT et al. (2020) Yes -
5 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
6 Support - Alonso-Gonzalez A et al. (2021) Yes -
7 Recent Recommendation - Steele JL et al. (2021) Yes ADHD, epilepsy/seizures
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2497A>T p.Lys833Ter stop_gained Familial - - 28831199 Li J , et al. (2017)
c.1366G>A p.Val456Met missense_variant Familial - - 28831199 Li J , et al. (2017)
c.1051C>T p.Arg351Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5051C>T p.Ser1684Leu missense_variant Familial - - 28831199 Li J , et al. (2017)
c.3640C>T p.Arg1214Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1928+1G>A - splice_site_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.4970G>A p.Arg1657Gln missense_variant De novo - - 34740135 Steele JL et al. (2021)
c.5156+1G>T p.? splice_site_variant Familial Maternal - 34740135 Steele JL et al. (2021)
c.1828G>A p.Gly610Arg missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.2454C>T p.Thr818= missense_variant Unknown - Multiplex 31130284 Monies D , et al. (2019)
c.3407T>C p.Leu1136Pro missense_variant Familial Maternal - 34740135 Steele JL et al. (2021)
c.3441+4C>G - splice_region_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.2113C>T p.Arg705Trp missense_variant Familial Maternal Simplex 32193494 Tran KT et al. (2020)
c.800C>T p.Ala267Val missense_variant Familial Maternal Simplex 32530565 Suzuki T et al. (2020)
c.653T>C p.Leu218Ser missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.1143G>C p.Gln381His missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.2342C>G p.Ala781Gly missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.4250C>T p.Thr1417Ile missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.4601G>A p.Arg1534His missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.4616C>G p.Thr1539Ser missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.5023A>G p.Thr1675Ala missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.5041C>A p.His1681Asn missense_variant Familial Maternal Simplex 34740135 Steele JL et al. (2021)
c.1400T>A p.Leu467His missense_variant Familial Maternal Multiplex 34740135 Steele JL et al. (2021)
c.2041G>A p.Glu681Lys missense_variant Familial Maternal Multiplex 34740135 Steele JL et al. (2021)
c.2363C>T p.Ala788Val missense_variant Familial Maternal Multiplex 34740135 Steele JL et al. (2021)
c.2494C>A p.Gln832Lys missense_variant Familial Maternal Multiplex 34740135 Steele JL et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
7/1/2020
3
icon
3

Decreased from 3 to 3

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
4/1/2020
3
icon
3

Decreased from 3 to 3

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Reports Added
[Genetic landscape of autism spectrum disorder in Vietnamese children2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
7/1/2017
icon
4

Increased from to 4

Description

A de novo splice-site variant in the PLXNA3 gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified three rare deleterious variants in PLXNA3 in Chinese ASD probands; subsequent Transmission and De Novo Association (TADA) analysis of a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, identified PLXNA3 as an ASD candidate gene with a PTADA of 0.006567.

Krishnan Probability Score

Score 0.49339176211639

Ranking 4181/25841 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 0.98311279329395

Ranking 2041/18225 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 0.94965881829976

Ranking 18180/18665 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
Zhang D Score

Score -0.076667793795955

Ranking 11441/20870 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
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