Human Gene Module / Chromosome 2 / SH3RF3

SH3RF3SH3 domain containing ring finger 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
4 / 0
Aliases
SH3RF3, POSH2,  SH3MD4
Associated Syndromes
-
Chromosome Band
2q13
Associated Disorders
-
Relevance to Autism

A de novo damaging missense variant in the SH3RF3 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a de novo likely gene-disruptive variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified SH3RF3 as a gene with a false discovery rate 0.2. Yuan et al., 2025 observed that genetic ablation of Sh3rf3 in mice resulted in disruption in the interaction between BRSK1/SAD-B and the ASD-associated active zone protein RIM1 leading to reduced RIM1 phosphorylation, synaptic dysfunction marked by a substantial reduction in both total synaptic vesicle (SV) density and readily releasable pool size coupled with delayed SV replenishment kinetics, and impaired excitatory synaptic transmission in the prefrontal cortex, which disturbed the excitatory-inhibitory (E/I) balance and elicited autistic-like behaviors in mice.

Molecular Function

Enables ubiquitin protein ligase activity. Involved in positive regulation of JNK cascade and protein autoubiquitination.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to SH3RF3 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
3 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
4 Support - Suhua Chang et al. () Yes -
5 Support - Yuting Yuan et al. () Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2485C>T p.Arg829Cys missense_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.2608C>T p.Arg870Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1544del p.Phe515SerfsTer6 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.114_131del p.Ala39_Glu44del inframe_deletion De novo - Simplex 39126614 Suhua Chang et al. ()
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo damaging missense variant in the SH3RF3 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a de novo likely gene-disruptive variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified SH3RF3 as a gene with a false discovery rate 0.2.

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo damaging missense variant in the SH3RF3 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a de novo likely gene-disruptive variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified SH3RF3 as a gene with a false discovery rate 0.2.

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

A de novo damaging missense variant in the SH3RF3 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a de novo likely gene-disruptive variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified SH3RF3 as a gene with a false discovery rate 0.2.

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
icon
3

Increased from to 3

New Scoring Scheme
Description

A de novo damaging missense variant in the SH3RF3 gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a de novo likely gene-disruptive variant in this gene was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified SH3RF3 as a gene with a false discovery rate 0.2.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.4629314149223

Ranking 9293/25841 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 0.98110087172834

Ranking 2100/18225 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 0.75340447353293

Ranking 1589/18665 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 0.36463271021993

Ranking 1852/20870 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
Submit New Gene

Report an Error