Human Gene Module / Chromosome 9 / PAX5

PAX5Paired box 5

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
4 / 0
Aliases
PAX5, ALL3,  BSAP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
9p13.2
Associated Disorders
-
Relevance to Autism

De novo loss-of-function variants in the PAX5 gene have been identified in two simplex ASD cases (Iossifov et al., 2014; O'Roak et al., 2014).

Molecular Function

May play an important role in B-cell differentiation as well as neural development and spermatogenesis.

Reports related to PAX5 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Recurrent de novo mutations implicate novel genes underlying simplex autism risk. O'Roak BJ , et al. (2014) Yes -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.46G>C p.Gly16Arg missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.385G>A p.Val129Met missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.76dupG p.Val26GlyfsTer49 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.333delC p.Trp112GlyfsTer47 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Score Delta: Score remained at 3

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.

1/1/2019
3
icon
3

Score remained at 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

1/1/2016
3
icon
3

Score remained at 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Krishnan Probability Score

Score 0.49402694853886

Ranking 3863/25841 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.
ExAC Score

Score 0.98424398873027

Ranking 2009/18225 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
Iossifov Probability Score

Score 0.812

Ranking 225/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.45455840801665

Ranking 360/18665 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).
Larsen Cumulative Evidence Score

Score 19

Ranking 109/461 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.
Zhang D Score

Score -0.16692564529118

Ranking 14617/20870 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.
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