Human Gene Module / Chromosome 17 / PRPF8

PRPF8pre-mRNA processing factor 8

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
8 / 9
Rare Variants / Common Variants
24 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
17p13.3
Associated Disorders
-
Relevance to Autism

De novo variants in the PRPF8 gene have been identified in ASD probands, including a de novo splice-site variant in a proband from a simplex family and several de novo missense variants (Iossifov et al., 2014; Krumm et al., 2015; Sanders et al., 2015; Yuen et al., 2017; Takata et al., 2018; da Silva Montenegro et al., 2020). Meta-analysis of 13,754 previously published NDD probands and 2,299 controls in da Silva Montenegro et al., 2020 identified six additional patients with validated de novo variants in PRPF8, and a comparison of de novo variants with a previously established mutational rate model found that PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test). O'Grady et al., 2022 reported 12 individuals with heterozygous variants in PRPF8 presenting with a neurodevelopmental syndrome characterized by some degree of intellectual disability or developmental delay, hypotonia, structural cardiac abnormalities, feeding difficulties, behavioral issues, abnormal brain MRI, and dysmorphic features; a diagnosis of ASD was made in approximately half of the individuals in this study.

Molecular Function

Pre-mRNA splicing occurs in 2 sequential transesterification steps. The protein encoded by this gene is a component of both U2- and U12-dependent spliceosomes, and found to be essential for the catalytic step II in pre-mRNA splicing process. It contains several WD repeats, which function in protein-protein interactions. This protein has a sequence similarity to yeast Prp8 protein. This gene is a candidate gene for autosomal dominant retinitis pigmentosa (retinitis pigmentosa 13; OMIM 600059).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PRPF8 (9 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 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , 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 Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Support Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort da Silva Montenegro EM , et al. (2019) Yes -
7 Recent Recommendation - O&#x27 et al. (2022) No ASD, epilepsy/seizures
8 Support - Zhou X et al. (2022) Yes -
9 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.101-43del - intron_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.40G>A p.Val14Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4785+22A>G - intron_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2966A>G p.Asp989Gly missense_variant De novo - - 35543142 O&#x27 et al. (2022)
c.3017C>T p.Ala1006Val missense_variant De novo - - 35543142 O&#x27 et al. (2022)
c.5552C>T p.Ser1851Phe missense_variant De novo - - 35543142 O&#x27 et al. (2022)
c.5594G>C p.Arg1865Thr missense_variant De novo - - 35543142 O&#x27 et al. (2022)
c.5633A>G p.Asp1878Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5138+280C>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1984+1G>C - splice_site_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.883G>A p.Glu295Lys missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.3890C>A p.Thr1297Lys missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.4204C>T p.Arg1402Cys missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.4381G>C p.Asp1461His missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.5353G>A p.Val1785Ile missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.6698G>C p.Ser2233Thr missense_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.4733G>A p.Arg1578Gln missense_variant Familial Maternal - 35543142 O&#x27 et al. (2022)
c.644A>G p.Asp215Gly missense_variant Unknown Not maternal - 35543142 O&#x27 et al. (2022)
c.5230C>T p.Arg1744Cys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1003C>T p.Pro335Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1897G>A p.Gly633Ser missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.6379dup p.Tyr2127LeufsTer10 frameshift_variant De novo - Simplex 35543142 O&#x27 et al. (2022)
c.6010C>T p.Gln2004Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4712T>G p.Ile1571Ser missense_variant De novo - Simplex 31696658 da Silva Montenegro EM , et al. (2019)
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
3

Increased from to 3

Krishnan Probability Score

Score 0.48018478491175

Ranking 8079/25841 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 0.99999999921923

Ranking 95/18225 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 0.8658538161922

Ranking 4105/18665 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 0.35084653985968

Ranking 2000/20870 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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