Human Gene Module / Chromosome 10 / POLR3A

POLR3ARNA polymerase III subunit A

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
7 / 14
Rare Variants / Common Variants
20 / 0
Aliases
POLR3A, ADDH,  C160,  HLD7,  RPC1,  RPC155,  WDRTS,  hRPC155
Associated Syndromes
-
Chromosome Band
10q22.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

Rare de novo variants in the POLR3A gene, including a splice-site variant, have been identified in ASD probands from multiple studies (Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017), while de novo variants in this gene have also been identified in probands presenting with intellectual disability or developmental delay (Lelieveld et al., 2016; Deciphering Developmental Disorder Study 2017). Biallelic variants in the POLR3A gene are responsible for hypomyelinating leukodystrophy-7 (HLD7; OMIM 607694), an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression (Bernard et al., 2011); a case with POLR3A-associated hypomyelinating leukodystrophy was recently described that also presented with developmental delay, intellectual disability, autism spectrum disorder, and hypodontia (Hiraide et al., 2020).

Molecular Function

The protein encoded by this gene is the catalytic component of RNA polymerase III, which synthesizes small RNAs. The encoded protein also acts as a sensor to detect foreign DNA and trigger an innate immune response.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to POLR3A (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy Bernard G et al. (2011) No -
2 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
5 Primary Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
7 Recent Recommendation Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy Hiraide T et al. (2020) No ASD, DD, ID
8 Support - Hiraide T et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
11 Support - Amerh S Alqahtani et al. (2023) No -
12 Support - Shenglan Li et al. (2024) No Dementia
13 Support - Axel Schmidt et al. (2024) No -
14 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1909+6T>C - intron_variant De novo - Simplex 28135719 et al. (2017)
c.1909+22G>A - intron_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2479-375G>A - intron_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.2901+1440G>A - intron_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.3342C>T p.Ser1114= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2787+988G>A - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.645+312C>T - intron_variant Familial Maternal - 32483275 Hiraide T et al. (2020)
c.1771-6C>G - splice_region_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.4108C>T p.Pro1370Ser missense_variant De novo - Simplex 28135719 et al. (2017)
c.3429+1G>A - splice_site_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2425G>A p.Val809Met missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2131A>T p.Lys711Ter stop_gained De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.1771-7C>G - splice_region_variant Familial Paternal - 38593811 Shenglan Li et al. (2024)
c.1451G>A p.Arg484Gln missense_variant Familial Paternal - 32483275 Hiraide T et al. (2020)
c.3892-297_3892-221del - intron_variant Familial Maternal - 38593811 Shenglan Li et al. (2024)
c.1771-6C>G - splice_region_variant Familial Maternal Simplex 33644862 Hiraide T et al. (2021)
c.1896_1897del p.Ala633GlnfsTer2 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.643C>T p.Gln215Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.791C>T p.Pro264Leu missense_variant Familial Paternal Simplex 33644863 Oliveira ECV et al. (2021)
c.1909+22G>A - intron_variant Familial Both parents Multiplex 37799141 Amerh S Alqahtani et al. (2023)
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 0.44531437540702

Ranking 15459/25841 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 7.3850509946394E-14

Ranking 17528/18225 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 0.82712954694646

Ranking 2777/18665 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 0.23770921600403

Ranking 3656/20870 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
Submit New Gene

Report an Error