Human Gene Module / Chromosome 17 / POLR2A

POLR2ARNA polymerase II subunit A

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
7 / 12
Rare Variants / Common Variants
38 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
-
Relevance to Autism

De novo missense variants in the POLR2A gene have been identified in ASD probands from the Autism Sequencing Consortium (Neale et al., 2012; Satterstrom et al., 2020) and the MSSNG cohort (Yuen et al., 2017). Heterozygous variants in the POLR2A gene are responsible for neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB; OMIM 618603), a neurodevelopmental disorder characterized by characterized by early-onset hypotonia, delayed walking, poor speech, and impaired intellectual development; autistic behavior or autism spectrum disorder was reported in a subset of affected individuals (Haijes et al., 2019; Hansen et al., 2021). More recently, Evans et al., 2022 described a 31-year-old female with complex autism spectrum disorder involving epilepsy, strabismus, and self-injurious behavior who was identified with a novel de novo and potentially damaging missense variant in the POLR2A gene.

Molecular Function

This gene encodes the largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene contains a carboxy terminal domain composed of heptapeptide repeats that are essential for polymerase activity. These repeats contain serine and threonine residues that are phosphorylated in actively transcribing RNA polymerase. In addition, this subunit, in combination with several other polymerase subunits, forms the DNA binding domain of the polymerase, a groove in which the DNA template is transcribed into RNA.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to POLR2A (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support - Haijes HA et al. (2019) No ASD or autistic behavior, ID, epilepsy/seizures
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Hansen AW et al. (2021) No ASD, epilepsy/seizures
7 Recent Recommendation - Evans DR et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Recent Recommendation - Timberlake AT et al. (2023) No ASD
10 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
11 Support - Karthika Ajit Valaparambil et al. () No -
12 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1275T>G p.Asp425Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1861A>C p.Ile621Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.83C>G p.Pro28Arg missense_variant Unknown - - 33665635 Hansen AW et al. (2021)
c.93+5036C>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1943C>A p.Ser648Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1367T>C p.Val456Ala missense_variant De novo - - 35328024 Evans DR et al. (2022)
c.323G>A p.Arg108His missense_variant Unknown - - 33665635 Hansen AW et al. (2021)
c.418C>T p.Arg140Trp missense_variant Unknown - - 33665635 Hansen AW et al. (2021)
c.2306T>C p.Met769Thr missense_variant De novo - - 31353023 Haijes HA et al. (2019)
c.2543T>C p.Ile848Thr missense_variant De novo - - 31353023 Haijes HA et al. (2019)
c.4768T>A p.Ser1590Thr missense_variant De novo - - 22495311 Neale BM , et al. (2012)
c.3275C>T p.Ala1092Val missense_variant Unknown - - 33665635 Hansen AW et al. (2021)
c.3281C>T p.Ser1094Phe missense_variant De novo - - 33665635 Hansen AW et al. (2021)
c.3407C>T p.Thr1136Ile missense_variant De novo - - 33665635 Hansen AW et al. (2021)
c.3752A>G p.Asn1251Ser missense_variant De novo - - 33665635 Hansen AW et al. (2021)
c.4252G>A p.Gly1418Arg missense_variant De novo - - 33665635 Hansen AW et al. (2021)
c.2098C>T p.Gln700Ter stop_gained De novo - Simplex 31353023 Haijes HA et al. (2019)
c.2203C>T p.Gln735Ter stop_gained De novo - Simplex 31353023 Haijes HA et al. (2019)
c.1423C>T p.Arg475Cys missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.4985C>A p.Pro1662His missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1112C>T p.Pro371Leu missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.1370T>C p.Ile457Thr missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.1592A>G p.Asn531Ser missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.2207C>T p.Thr736Met missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.93+4119_93+4129del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3325T>C p.Tyr1109His missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.3371T>C p.Leu1124Pro missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.3752A>G p.Asn1251Ser missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.4808G>A p.Arg1603His missense_variant De novo - Simplex 31353023 Haijes HA et al. (2019)
c.2361C>T p.Val787= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5298dup p.Pro1767ThrfsTer7 frameshift_variant De novo - - 31353023 Haijes HA et al. (2019)
c.3442G>A p.Ala1148Thr missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1314_1319del p.His439_Leu440del inframe_deletion De novo - - 33665635 Hansen AW et al. (2021)
c.2006_2008del p.Tyr669del inframe_deletion De novo - Simplex 31353023 Haijes HA et al. (2019)
c.2262_2264del p.Ser755del inframe_deletion De novo - Simplex 31353023 Haijes HA et al. (2019)
c.3373_3375del p.Lys1125del inframe_deletion De novo - Simplex 31353023 Haijes HA et al. (2019)
c.1424G>A p.Arg475His missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.5440_5441del p.Gln1814ValfsTer99 frameshift_variant Familial Maternal - 33665635 Hansen AW et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.51596543888556

Ranking 1753/25841 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 0.99999994210215

Ranking 177/18225 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
Iossifov Probability Score

Score 0.97

Ranking 59/239 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
Original Source
Sanders TADA Score

Score 0.94914378351926

Ranking 17971/18665 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 0.1625999427029

Ranking 4934/20870 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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