Human Gene Module / Chromosome 10 / SMC3

SMC3structural maintenance of chromosomes 3

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 14
Rare Variants / Common Variants
27 / 0
Aliases
SMC3, BAM,  BMH,  CDLS3,  CSPG6,  HCAPL1, SMC3
Associated Syndromes
Cornelia de Lange syndrome-3 (CDLS3)
Chromosome Band
10q25.2
Associated Disorders
-
Relevance to Autism

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed).

Molecular Function

Central component of cohesin, a complex required for chromosome cohesion during the cell cycle.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMC3 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation Deardorff MA , et al. (2007) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes Gil-Rodrguez MC , et al. (2015) No -
5 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
6 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
7 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
8 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
9 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No -
10 Support - Mahjani B et al. (2021) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Spataro N et al. (2023) No -
13 Support - Wang J et al. (2023) Yes -
14 Support - Morad Ansari et al. (2024) No ASD, ADD, ADHD, ID, epilepsy/seizures
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 38297832 Morad Ansari et al. (2024)
- - copy_number_loss Familial Paternal - 38297832 Morad Ansari et al. (2024)
- - copy_number_loss Unknown Not maternal - 38297832 Morad Ansari et al. (2024)
c.430-1G>T - splice_site_variant De novo - - 38297832 Morad Ansari et al. (2024)
c.2372T>G p.Leu791Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.778C>T p.Gln260Ter stop_gained De novo - - 38297832 Morad Ansari et al. (2024)
c.1561C>T p.Arg521Ter stop_gained Unknown - - 38297832 Morad Ansari et al. (2024)
c.2899C>T p.Arg967Ter stop_gained De novo - - 38297832 Morad Ansari et al. (2024)
c.324G>C p.Gln108His missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.283G>A p.Glu95Lys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2062_2064del p.Glu688del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.2005_2007del p.Tyr669del inframe_deletion De novo - - 36980980 Spataro N et al. (2023)
c.661C>T p.Arg221Ter stop_gained Familial Maternal - 38297832 Morad Ansari et al. (2024)
c.3035A>T p.Lys1012Ile missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1078C>T p.Arg360Ter stop_gained Familial Paternal - 38297832 Morad Ansari et al. (2024)
c.2413C>T p.Arg805Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1464_1466del p.Glu488del inframe_deletion De novo - - 17273969 Deardorff MA , et al. (2007)
c.3002_3004del p.Ile1001del inframe_deletion De novo - Simplex 37393044 Wang J et al. (2023)
c.1071_1074del p.Glu358AsnfsTer44 frameshift_variant De novo - - 31178897 Gao C , et al. (2019)
c.461dup p.Arg155GlufsTer12 frameshift_variant Unknown - - 38297832 Morad Ansari et al. (2024)
c.1539del p.Asn513LysfsTer4 frameshift_variant Unknown - - 38297832 Morad Ansari et al. (2024)
c.1892T>C p.Leu631Pro missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.1474_1478del p.Lys492AlafsTer5 frameshift_variant De novo - - 38297832 Morad Ansari et al. (2024)
c.3646_3647dup p.Gly1217MetfsTer39 frameshift_variant Unknown - - 38297832 Morad Ansari et al. (2024)
c.2412dup p.Arg805SerfsTer13 frameshift_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
TGAAAAGAA>TGAA - frameshift_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.3563G>C p.Gly1188Ala missense_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

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

Decreased from 4S to 4S

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
7/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodrguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodrguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with SMC3 mutations presented with autism spectrum disorder.

Reports Added
[Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.2018]
7/1/2017
4
icon
4S

Decreased from 4 to 4S

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017. Mutations in the SMC3 gene are associated with a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 3; OMIM 610759) (Deardorff et al., 2007; Gil-Rodríguez et al., 2015). Phenotypic characterization of 16 patients with Cornelia de Lange-like features caused by SMC3 variants in Gil-Rodríguez et al., 2015 demonstrated that, while intellectual disability was a prominent feature, behavioral problems were less frequently reported (1 individual presented with autism, whereas another presented with autistic features; poor eye contact, attention deficit disorder, aggression, and self-injurious behavior were also observed).

Reports Added
[Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation.2007] [De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.2015]
1/1/2017
icon
4

Increased from to 4

Description

A de novo likely gene disruptive (LGD) variant in SMC3 was identified in an ASD proband from the Autism Simplex Collection in Stessman et al., 2017.

Krishnan Probability Score

Score 0.50168859867179

Ranking 2009/25841 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 0.99999999949759

Ranking 88/18225 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 0.79349148547812

Ranking 2100/18665 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 0.35025904787074

Ranking 2005/20870 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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