Human Gene Module / Chromosome 9 / RNF38

RNF38ring finger protein 38

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 2
Rare Variants / Common Variants
2 / 0
Aliases
-
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
9p13.2
Associated Disorders
-
Relevance to Autism

A de novo splice-site variant in the RNF38 gene was identified in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified a rare inherited damaging missense variant in this gene in a Chinese ASD proband. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD cases and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified RNF38 as an ASD candidate gene with a PTADA of 0.009043.

Molecular Function

This gene encodes a protein with a coiled-coil motif and a RING-H2 motif (C3H2C2) at its carboxy-terminus. The RING motif is a zinc-binding domain found in a large set of proteins playing roles in diverse cellular processes including oncogenesis, development, signal transduction, and apoptosis. The protein encoded by the RNF38 gene acts as an E3 ubiquitin-protein ligase able to ubiquitinate p53/TP53 which promotes its relocalization to discrete foci associated with PML nuclear bodies.

Reports related to RNF38 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.619C>A p.Pro207Thr missense_variant Familial - - 28831199 Li J , et al. (2017)
c.356+2T>C - splice_site_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

A de novo splice-site variant in the RNF38 gene was identified in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified a rare inherited damaging missense variant in this gene in a Chinese ASD proband. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD cases and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified RNF38 as an ASD candidate gene with a PTADA of 0.009043.

Score Delta: Decreased from 4 to 3

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo splice-site variant in the RNF38 gene was identified in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified a rare inherited damaging missense variant in this gene in a Chinese ASD proband. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD cases and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified RNF38 as an ASD candidate gene with a PTADA of 0.009043.

Reports Added
[New Scoring Scheme]
7/1/2017
icon
4

Increased from to 4

Description

A de novo splice-site variant in the RNF38 gene was identified in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified a rare inherited damaging missense variant in this gene in a Chinese ASD proband. Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of Chinese ASD cases and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified RNF38 as an ASD candidate gene with a PTADA of 0.009043.

Krishnan Probability Score

Score 0.60954115461416

Ranking 254/25841 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.
ExAC Score

Score 0.99939025689205

Ranking 973/18225 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
Sanders TADA Score

Score 0.40547928369515

Ranking 286/18665 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).
Zhang D Score

Score 0.36272097971451

Ranking 1867/20870 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.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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