Human Gene Module / Chromosome 1 / CHRM3

CHRM3cholinergic receptor muscarinic 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
7 / 1
Aliases
CHRM3, EGBRS,  HM3
Associated Syndromes
-
Chromosome Band
1q43
Associated Disorders
-
Relevance to Autism

A 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, repetitive stereotypic behaviors including self-injurious head banging and hair pulling, and no seizures, anxiety, or mood swings (Petersen et al., 2012).

Molecular Function

The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue.

External Links
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Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CHRM3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature Perrone MD , et al. (2011) No -
2 Primary Deletion 1q43 encompassing only CHRM3 in a patient with autistic disorder Petersen AK , et al. (2012) Yes -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
5 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
6 Support Constitutional 763.3 Kb chromosome 1q43 duplication encompassing only CHRM3 gene identified by next generation sequencing (NGS) in a child with intellectual disability Cheng X , et al. (2019) Yes -
7 Support - Chen WX et al. (2022) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Simplex 31019551 Cheng X , et al. (2019)
- - copy_number_loss De novo - Simplex 22186213 Perrone MD , et al. (2011)
- - copy_number_loss Unknown - Unknown 23253743 Petersen AK , et al. (2012)
c.1762C>T p.Gln588Ter stop_gained Familial - Simplex 28831199 Li J , et al. (2017)
c.1423A>T p.Ile475Phe missense_variant De novo - Simplex 28831199 Li J , et al. (2017)
c.1504A>G p.Ile502Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.824C>T p.Ala275Val missense_variant De novo - Simplex 36320054 Chen WX et al. (2022)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
C>A - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

A 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, and repetitive stereotypic behaviors including self-injurious head banging and hair pulling in Petersen et al., 2013. A de novo 911 kb deletion encompassing CHRM3 and two other genes had previously been identified in a 7-year-old male patient with intellectual disability/developmental delay and autistic features in Perrone et al., 2012. Two de novo missense variants and one inherited nonsense variant in this gene have been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

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 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, and repetitive stereotypic behaviors including self-injurious head banging and hair pulling in Petersen et al., 2013. A de novo 911 kb deletion encompassing CHRM3 and two other genes had previously been identified in a 7-year-old male patient with intellectual disability/developmental delay and autistic features in Perrone et al., 2012. Two de novo missense variants and one inherited nonsense variant in this gene have been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, and repetitive stereotypic behaviors including self-injurious head banging and hair pulling in Petersen et al., 2013. A de novo 911 kb deletion encompassing CHRM3 and two other genes had previously been identified in a 7-year-old male patient with intellectual disability/developmental delay and autistic features in Perrone et al., 2012. Two de novo missense variants and one inherited nonsense variant in this gene have been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

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

Decreased from 4 to 4

Description

A 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, and repetitive stereotypic behaviors including self-injurious head banging and hair pulling in Petersen et al., 2013. A de novo 911 kb deletion encompassing CHRM3 and two other genes had previously been identified in a 7-year-old male patient with intellectual disability/developmental delay and autistic features in Perrone et al., 2012. Two de novo missense variants and one inherited nonsense variant in this gene have been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Reports Added
[Constitutional 763.3 Kb chromosome 1q43 duplication encompassing only CHRM3 gene identified by next generation sequencing (NGS) in a child with int...2019]
10/1/2017
icon
4

Increased from to 4

Description

A 473 kb deletion harboring the CHRM3 gene was identified in a male patient with autistic disorder who had social withdrawal, eating problems, and repetitive stereotypic behaviors including self-injurious head banging and hair pulling in Petersen et al., 2013. A de novo 911 kb deletion encompassing CHRM3 and two other genes had previously been identified in a 7-year-old male patient with intellectual disability/developmental delay and autistic features in Perrone et al., 2012. Two de novo missense variants and one inherited nonsense variant in this gene have been identified in ASD probands (De Rubeis et al., 2014; Li et al., 2017).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
Krishnan Probability Score

Score 0.53823124808051

Ranking 1462/25841 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 0.93702612820882

Ranking 2866/18225 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 0.93869687787546

Ranking 13952/18665 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 -0.050244329111086

Ranking 10431/20870 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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