Human Gene Module / Chromosome 17 / RNF135

RNF135Ring finger protein 135

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
9 / 1
Aliases
RNF135, L13,  MMFD,  REUL,  Riplet
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
17q11.2
Associated Disorders
-
Relevance to Autism

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the. p.Arg115Lys variant (Tastet et al., 2015). Furthermore, two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

Molecular Function

The protein encoded by this gene acts as an E2-dependent E3 ubiquitin-protein ligase. It is located in the 17q11.2 chromosomal region, which is known to be frequently deleted in patients with neurofibromatosis, and heterozygous mutations in the RNF135 gene are associated with macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD; OMIM 614192).

Reports related to RNF135 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Douglas J , et al. (2007) No -
2 Primary Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism. Tastet J , et al. (2015) Yes -
3 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c... Zhou WZ , et al. (2019) Yes -
4 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Stereotypies
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Unknown 17632510 Douglas J , et al. (2007)
c.834+309del - frameshift_variant Familial Paternal - 30763456 Zhou WZ , et al. (2019)
c.1015delG p.Val339fs frameshift_variant Familial Paternal - 30763456 Zhou WZ , et al. (2019)
c.*219del - frameshift_variant Familial Maternal Multi-generational 17632510 Douglas J , et al. (2007)
c.*219del - frameshift_variant Familial Paternal Multi-generational 17632510 Douglas J , et al. (2007)
c.727C>T p.Gln243Ter stop_gained Familial Maternal Multi-generational 17632510 Douglas J , et al. (2007)
c.857G>A p.Arg286His missense_variant Familial Paternal Multi-generational 17632510 Douglas J , et al. (2007)
c.834+130del - splice_site_variant Unknown - Not simplex (positive family history) 31130284 Monies D , et al. (2019)
c.807del p.Ser270GlnfsTer16 frameshift_variant Familial Paternal Multi-generational 17632510 Douglas J , et al. (2007)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.344G>A p.Arg115Lys missense_variant - - - 26368817 Tastet J , et al. (2015)
SFARI Gene score
3S

Suggestive Evidence, Syndromic

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the p.Arg115Lys variant (Tastet et al., 2015). Mutations in RNF135 are responsible for macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD, OMIM 614192); two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

Score Delta: Decreased from 4S to 3S

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.

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."

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the p.Arg115Lys variant (Tastet et al., 2015). Mutations in RNF135 are responsible for macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD, OMIM 614192); two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the p.Arg115Lys variant (Tastet et al., 2015). Mutations in RNF135 are responsible for macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD, OMIM 614192); two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

1/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the p.Arg115Lys variant (Tastet et al., 2015). Mutations in RNF135 are responsible for macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD, OMIM 614192); two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

10/1/2015
icon
4S

Increased from to 4S

Description

Genetic analysis of RNF135 in a French ASD cohort found a significant increase in the frequency of genotypes carrying the p.Arg115Lys missense variant in cases compared to controls (P=0.0019, odds ratio 4.23), including three unrelated patients that were homozygous for the p.Arg115Lys variant (Tastet et al., 2015). Mutations in RNF135 are responsible for macrocephaly, macrosomia, and facial dysmorphism syndrome (MMFD, OMIM 614192); two of the six MMFD probands with RNF135 mutations described in Douglas et al., 2007 also presented with autistic spectrum disorder.

Krishnan Probability Score

Score 0.3424392694659

Ranking 24280/25841 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 0.0030751661550514

Ranking 10972/18225 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 0.94224095576854

Ranking 15232/18665 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 -0.40290534113815

Ranking 18403/20870 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.
CNVs associated with RNF135(1 CNVs)
17q11.2 22 Deletion-Duplication 36  /  98
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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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