Human Gene Module / Chromosome 11 / POLA2

POLA2DNA polymerase alpha 2, accessory subunit

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 7
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
11q13.1
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the POLA2 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene were identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 2/84,448 expected; hypergeometric P-value of 4.6E-05).

Molecular Function

May play an essential role at the early stage of chromosomal DNA replication by coupling the polymerase alpha/primase complex to the cellular replication machinery.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to POLA2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
3 Support - Woodbury-Smith M et al. (2022) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Yuan B et al. (2023) Yes -
6 Support - Wang J et al. (2023) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.157C>T p.His53Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.443C>A p.Pro148Gln missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.737C>A p.Pro246Gln missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1249G>C p.Gly417Arg missense_variant De novo - Multiplex 28714951 Lim ET , et al. (2017)
c.877G>A p.Glu293Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1467C>T p.Ser489= synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1078del p.Leu360CysfsTer4 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant in the POLA2 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene were identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 2/84,448 expected; hypergeometric P-value of 4.6E-05).

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 missense variant in the POLA2 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene were identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 2/84,448 expected; hypergeometric P-value of 4.6E-05).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo missense variant in the POLA2 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene were identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 2/84,448 expected; hypergeometric P-value of 4.6E-05).

Reports Added
[New Scoring Scheme]
7/1/2017
icon
4

Increased from to 4

Description

A de novo missense variant in the POLA2 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene were identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 2/84,448 expected; hypergeometric P-value of 4.6E-05).

Krishnan Probability Score

Score 0.32729918729611

Ranking 25244/25841 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 0.0002159590604807

Ranking 12675/18225 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 0.87876511208678

Ranking 4770/18665 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 -0.43131278753245

Ranking 18647/20870 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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