Human Gene Module / Chromosome 3 / SETD5

SETD5SET domain containing 5

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 16
Rare Variants / Common Variants
48 / 0
Aliases
SETD5, 
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
3p25.3
Associated Disorders
ASD
Relevance to Autism

Seven loss-of-function variants, five of which were confirmed de novo in origin, were identified in the SETD5 gene following screening of 996 individuals with intellectual disability; behavioral problems, including OCD, hand flapping with ritualized behavior, and ASD, were prominent features in affected individuals (Grozeva et al., 2014).

Molecular Function

This gene is predicted to encode a methyltransferase and resides within the critical interval for the 3p25 microdeletion syndrome.

Reports related to SETD5 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No -
4 Support Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region. Kellogg G , et al. (2013) No -
5 Primary De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa... Grozeva D , et al. (2014) No OCD, ASD
6 Support Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Pinto D , et al. (2014) Yes -
7 Support Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Kuechler A , et al. (2014) No -
8 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
10 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
11 Support Mutations in HECW2 are associated with intellectual disability and epilepsy. Halvardson J , et al. (2016) No -
12 Support SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression. Szczauba K , et al. (2016) No -
13 Support Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose... Farwell Hagman KD , et al. (2016) No -
14 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
15 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) No -
16 Support SETD5 gene variant associated with mild intellectual disability - a case report. Stur E , et al. (2017) No -
Rare Variants   (48)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.2005G>A p.Gly669Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2752C>T p.Arg768Ter stop_gained De novo - Simplex 23020937 Rauch A , et al. (2012)
c.1195A>T p.Lys399Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.1333C>T p.Arg445Ter stop_gained Unknown Not maternal Multiplex 24680889 Grozeva D , et al. (2014)
c.1866C>G p.Tyr622Ter stop_gained Unknown Not maternal Simplex 24680889 Grozeva D , et al. (2014)
c.2177_2178del p.Thr726AsnfsTer39 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.3001C>T p.Arg1001Ter stop_gained De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.3771dup p.Ser1258GlufsTer65 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
c.3856del p.Ser1286LeufsTer84 frameshift_variant De novo - Simplex 24680889 Grozeva D , et al. (2014)
- - copy_number_loss De novo - Unknown 24768552 Pinto D , et al. (2014)
- - splice_site_variant De novo - Simplex 25138099 Kuechler A , et al. (2014)
c.922C>T p.Arg308Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1405G>A p.Val469Ile missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3773G>C p.Ser1258Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2054G>A p.Arg685His missense_variant Familial Paternal (n=1), maternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.1712G>C p.Gly571Ala missense_variant Familial Paternal (n=2), maternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.1712G>C p.Gly571Ala missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2359T>C p.Tyr787His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3174G>C p.Gln1058His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3523A>C p.Ser1175Arg missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.31A>G p.Thr11Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2174A>G p.Asp725Gly missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1374A>T p.Glu458Asp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1550C>T p.Pro517Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3787G>T p.Val1263Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3821C>T p.Thr1274Ile missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.304G>T p.Glu102Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.728G>A p.Arg243His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2054G>A p.Arg685His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3011G>A p.Gly1004Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3233G>A p.Arg1078Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3635C>T p.Ser1212Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.658T>C p.Phe220Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1870C>G p.Pro624Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2351G>A p.Arg784Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2999T>G p.Phe1000Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3613G>A p.Ala1205Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.367C>T p.Arg123Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2307G>T p.Arg769Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2920G>C p.Asp974His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3154G>T p.Gly1052Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.2158G>T p.Glu720Ter stop_gained De novo - Simplex 27334371 Halvardson J , et al. (2016)
c.2918C>G p.Ser973Ter stop_gained Familial Paternal Multi-generational 27375234 Szczauba K , et al. (2016)
- p.Thr552AsnfsTer5 frameshift_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.1524+1G>A p.? splice_site_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.749G>A p.Arg250Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.3848_3849insC p.Ser1286Leufs frameshift_variant De novo - Simplex 28549204 Stur E , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

1

High Confidence

See all Category 1 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.

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."

04-01-2017
1S

Initial score established: 1S

Description

Seven loss-of-function variants in the SETD5 gene, five of which were confirmed as de novo in origin, were identified in affected individuals following screening of 996 individuals with ID; two individuals with de novo LoF SETD5 variants were also identified as “autistic” in the supplementary material (PMID 24680889). A de novo LoF variant and a de novo likely damaging missense variant in the SETD5 gene were identified in two unrelated ASD probands from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified SETD5 as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.2016] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disa...2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.2013] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Mutations in HECW2 are associated with intellectual disability and epilepsy.2016] [Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome.2014] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [SETD5 gene variant associated with mild intellectual disability - a case report.2017] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [De novo gene disruptions in children on the autistic spectrum.2012]
CNVs associated with SETD5(1 CNVs)
3p25.3 17 Deletion-Duplication 29  /  86
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CEP70 centrosomal protein 70kDa Human Protein Binding 80321 Q8NHQ1
DPPA2 Developmental pluripotency-associated protein 2 Human Protein Binding 151871 Q7Z7J5
miR126-5p microRNA 126 Human RNA Binding 406913 N/A
miR1265p microRNA 126 Human RNA Binding 406913 N/A
PRR20E Proline-rich protein 20E Human Protein Binding 122183 P86478
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