Human Gene Module / Chromosome 19 / U2AF2

U2AF2U2 small nuclear RNA auxiliary factor 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 8
Rare Variants / Common Variants
29 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
19q13.42
Associated Disorders
-
Relevance to Autism

Li et al., 2023 reported 46 unrelated individuals with heterozygous missense or in-frame deletion variants in the U2AF2 gene, the majority of whom presented with developmental delay, intellectual disability, and facial dysmorphisms; autism or autistic features was reported in 11/25 (44%) of individuals in this cohort. Subsequent functional analysis in this report demonstrated that eight disease-associated U2AF2 missense variants dysregulated splicing of a model substrate, with two hyper-recurrent variants (p.Arg149Trp and p.Arg150Cys) being additionally shown to cause reduced neuritogenesis in neurons differentiated from human pluripotent stem cells, an impaired ability to rescue phenotypes in neural-specific U2af50 knockdown flies, and disruption of the Prp19 complex. A potentially deleterious de novo missense variant in the U2AF2 gene had previously been identified in an ASD proband from the SPARK cohort (Trost et al., 2022), and additional potentially deleterious missense variants in this gene have been observed in individuals with ASD or developmental delay (The Deciphering Developmental Disorders Study 2017; Wang et al., 2020).

Molecular Function

U2 auxiliary factor (U2AF), comprised of a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the U2AF large subunit which contains a sequence-specific RNA-binding region with 3 RNA recognition motifs and an Arg/Ser-rich domain necessary for splicing. The large subunit binds to the polypyrimidine tract of introns early during spliceosome assembly. Heterozygous mutations in this gene are responsible for developmental delay, dysmorphic facies, and brain anomalies (DEVDFB; OMIM 620535), a disorder characterized by global developmental delay with impaired intellectual development, speech delay, nonspecific dysmorphic facial features, hypotonia, and impaired overall growth with small head circumference (Hiraide et al., 2021; Wang et al., 2023; Kittock et al., 2023; Kuroda et al., 2023).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to U2AF2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
2 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
3 Support - Takuya Hiraide et al. (2021) No -
4 Support - Trost B et al. (2022) Yes -
5 Support - Xiaole Wang et al. (2023) No -
6 Support - Yukiko Kuroda et al. (2023) No -
7 Primary - Dong Li et al. (2024) No Autism or autistic features, ADHD/ADD, epilepsy/se
8 Support - Debanjana Maji et al. (2024) No -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.470C>T p.Pro157Leu missense_variant De novo - - 28135719 et al. (2017)
c.755C>T p.Thr252Ile missense_variant De novo - - 28135719 et al. (2017)
c.145C>T p.Arg49Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.154C>T p.Arg52Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.449G>A p.Arg150His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1282G>C p.Gly428Arg missense_variant De novo - - 36368308 Trost B et al. (2022)
c.1244G>A p.Arg415Gln missense_variant Unknown - - 37962958 Dong Li et al. (2024)
c.332A>G p.Gln111Arg missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.356C>T p.Thr119Ile missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.389T>C p.Leu130Pro missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.421G>A p.Gly141Arg missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.434C>T p.Thr145Ile missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.436A>G p.Arg146Gly missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.445C>T p.Arg149Trp missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.446G>A p.Arg149Gln missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.448C>T p.Arg150Cys missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.449G>A p.Arg150His missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.457G>A p.Val153Met missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.524T>C p.Leu175Pro missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.556G>A p.Val186Met missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.587A>C p.Asn196Thr missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.607C>T p.Arg203Cys missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.644A>G p.Asp215Gly missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.694T>C p.Tyr232His missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.742G>A p.Gly248Arg missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.761T>C p.Val254Ala missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.794G>A p.Gly265Asp missense_variant De novo - Simplex 37962958 Dong Li et al. (2024)
c.985_987del p.Lys329del inframe_deletion De novo - Simplex 37962958 Dong Li et al. (2024)
c.791G>A p.Gly264Glu missense_variant Unknown Not maternal - 37962958 Dong Li et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

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.

1/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.44238006310926

Ranking 17548/25841 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 0.99718884741604

Ranking 1343/18225 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 0.93670233107989

Ranking 13282/18665 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 0.30530175770323

Ranking 2662/20870 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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