Human Gene Module / Chromosome 2 / UBR3

UBR3ubiquitin protein ligase E3 component n-recognin 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
6 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
2q31.1
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the UBR3 gene was observed in both members of a monozyotic twin pair concordant for ASD from the south Indian state of Kerala and belonging to the Dravidian population in Anitha et al., 2024. Additional de novo variants in this gene, including a de novo frameshift variant, have been identified in ASD probands from the Simons Simplex Collection (Dong et al., 2014; Iossifov et al., 2014), while a de novo missense variant in this gene was more recently identified in a Chinese ASD proband (Wang et al., 2023). Wang et al., 2021 identified UBR3 as a novel candidate gene for neurodevelopmental disorders (NDDs) following an integrated analysis of 3,195 Chinese NDD probands and de novo mutations from 16,807 NDD probands from public datasets with a false discovery rate < 0.01. UBR3 was subsequently identified as a NDD risk gene with a 5% false discovery rate in Hamanaka et al., 2022 based in part of the contribution of de novo CNV data; in the case of UBR3, the de novo CNV in question was a deletion identified in an ASD proband from the Simons Simplex Collection.

Molecular Function

Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in several processes, including cellular protein metabolic process; sensory perception of smell; and suckling behavior. Predicted to act upstream of or within in utero embryonic development and olfactory behavior. Predicted to be integral component of membrane. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to UBR3 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder Dong S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support - Wang T et al. (2021) No -
4 Support - Hamanaka K et al. (2022) No ASD
5 Support - Wang J et al. (2023) Yes -
6 Primary - Ayyappan Anitha et al. (2024) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 35468861 Hamanaka K et al. (2022)
c.230C>G p.Ala77Gly missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.4482C>T p.His1494= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5029_5031del p.Glu1677del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.813_815delinsC p.Asn272ProfsTer22 frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.4528C>A p.Leu1510Ile missense_variant De novo - Multiplex (monozygotic twins) 39038432 Ayyappan Anitha et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

10/1/2024
2

Initial score established: 2

Krishnan Probability Score

Score 0.44772545393363

Ranking 12025/25841 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 0.99954912362798

Ranking 915/18225 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 0.57814220666878

Ranking 641/18665 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 0.5490049335317

Ranking 248/20870 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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