Human Gene Module / Chromosome 3 / CNTN3

CNTN3contactin 3

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
4 / 0
Aliases
CNTN3, BIG-1,  PANG,  PCS
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation
Chromosome Band
3p12.3
Associated Disorders
-
Relevance to Autism

A rare mutation in the CNTN3 gene has been identified in a patient with ASD (Vaags et al., 2012).

Molecular Function

Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity.

Reports related to CNTN3 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Identifying autism loci and genes by tracing recent shared ancestry. Morrow EM , et al. (2008) Yes -
2 Primary Rare deletions at the neurexin 3 locus in autism spectrum disorder. Vaags AK , et al. (2012) Yes -
3 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ... Brett M , et al. (2014) Yes MCA
4 Negative Association No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti... Murdoch JD , et al. (2015) Yes -
5 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Both parents Simplex 18621663 Morrow EM , et al. (2008)
c.2521C>T p.Arg841Trp missense_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.547A>T p.Ile183Leu missense_variant Familial Maternal Multiplex 24690944 Brett M , et al. (2014)
c.2600G>A p.Arg867Gln missense_variant Familial Paternal Simplex 22209245 Vaags AK , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

A homozygous deletion nearest to the 5' end of the CNTN3 gene was identified in an ASD proband; an unaffected sibling and both parents (first-cousins) were hemizygous for the deletion (Morrow et al., 2008). Inherited missense variants in the CNTN3 gene have also been identified in individuals with ASD (Vaags et al., 2012; Brett et al., 2014), while a rare de novo missense variant in this gene was identified in a proband with Tourette syndrome (Willsey et al., 2017).

Score Delta: Decreased from 4 to 3

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A homozygous deletion nearest to the 5' end of the CNTN3 gene was identified in an ASD proband; an unaffected sibling and both parents (first-cousins) were hemizygous for the deletion (Morrow et al., 2008). Inherited missense variants in the CNTN3 gene have also been identified in individuals with ASD (Vaags et al., 2012; Brett et al., 2014), while a rare de novo missense variant in this gene was identified in a proband with Tourette syndrome (Willsey et al., 2017).

Reports Added
[New Scoring Scheme]
10/1/2018
icon
4

Increased from to 4

Description

A homozygous deletion nearest to the 5' end of the CNTN3 gene was identified in an ASD proband; an unaffected sibling and both parents (first-cousins) were hemizygous for the deletion (Morrow et al., 2008). Inherited missense variants in the CNTN3 gene have also been identified in individuals with ASD (Vaags et al., 2012; Brett et al., 2014), while a rare de novo missense variant in this gene was identified in a proband with Tourette syndrome (Willsey et al., 2017).

Krishnan Probability Score

Score 0.49497143062244

Ranking 3302/25841 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 0.014141786255582

Ranking 9735/18225 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 0.88550104972887

Ranking 5192/18665 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).
Larsen Cumulative Evidence Score

Score 0

Ranking 440/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.41002402837347

Ranking 1348/20870 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.
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