Human Gene Module / Chromosome 4 / SH3RF1

SH3RF1SH3 domain containing ring finger 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
21 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4q32.3-q33
Associated Disorders
-
Relevance to Autism

De novo variants in the SH3RF1 gene, including a splice-site variant and an in-frame insertion variant, have been identified in ASD probands (Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020). Yao et al., 2022 found that the protein encoded by the SH3RF1 gene (called POSH in this report) interacted with PSD-95 (the protein encoded by the ASD candidate gene DLG4) and the proteins encoded by the SHANK2 and SHANK3 genes, and that these interactions were required for dendritic spine development; furthermore, SH3RF1 conditional knockout mice exhibited autism-like behaviors, deficits in learning and memory, and abnormal evoked NMDAR EPSCs and NMDAR-dependent plasticity.

Molecular Function

This gene encodes a protein containing an N-terminus RING-finger, four SH3 domains, and a region implicated in binding of the Rho GTPase Rac. Via the RING-finger, the encoded protein has been shown to function as an ubiquitin-protein ligase involved in protein sorting at the trans-Golgi network. The encoded protein may also act as a scaffold for the c-Jun N-terminal kinase signaling pathway, facilitating the formation of a functional signaling module.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SH3RF1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
3 Primary Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Recent Recommendation - Yao M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.766-5491G>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1068+2669G>A - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1180-1778A>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.393+46490A>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.393+13890C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.394-7794G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.766-5995T>C - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.766-7947G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.393+26561G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.393+48163del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.393+49188del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.394-16087G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.394-20476A>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.394-23628G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.394-54355G>A - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1248C>T p.Gly416%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2139+3254_2139+3256del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.393+37822_393+37826del - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.394-11234_394-11233insTCAAGATA - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.394-2_394-1insTCTGCAGAGCTCCCAGGGCGGACAGCAGCCTCGGGTGCAATCCTGGAGCCCCCCAGTGAG - splice_site_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2140-1_2140insGCTGAGCCCAGTGGCCGGATAGTGACCGTTCTCCCTGGACTCCCCACATCTCCTGACAGTGCTTCATCAGCTTGTGGGAACAGT p.Ala676_Lys713dup inframe_insertion De novo - - 31981491 Satterstrom FK et al. (2020)
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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.4072065263488

Ranking 23055/25841 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 0.04639552762363

Ranking 8633/18225 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 0.94176791181527

Ranking 15055/18665 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 -0.039140952746021

Ranking 10022/20870 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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