Human Gene Module / Chromosome 16 / CHMP1A

CHMP1Acharged multivesicular body protein 1A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
8 / 0
Aliases
CHMP1A, CHMP1,  PCH8,  PCOLN3,  PRSM1,  VPS46-1,  VPS46A
Associated Syndromes
-
Chromosome Band
16q24.3
Associated Disorders
-
Relevance to Autism

De novo damaging missense variants in the CHMP1A gene were identifed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function variants in this gene were observed in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CHMP1A as an ASD candidate gene with a PTADA of 0.001528.

Molecular Function

Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. Homozygous mutations in the CHMP1A gene are associated with pontocerebellar hypoplasia type 8 (PCH8; OMIM 614961), a neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects (Mochida et al., 2012).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CHMP1A (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development Mochida GH , et al. (2012) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.127C>T p.Arg43Ter stop_gained Familial - - 28831199 Li J , et al. (2017)
c.160C>T p.Arg54Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.202C>T p.Gln68Ter missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.127C>T p.Arg43Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.487C>T p.Arg163Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.487C>T p.Arg163Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.45C>T p.Gly15= missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.45C>T p.Gly15= missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo damaging missense variants in the CHMP1A gene were identifed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function variants in this gene were observed in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CHMP1A as an ASD candidate gene with a PTADA of 0.001528. Homozygous mutations in the CHMP1A gene are associated with pontocerebellar hypoplasia type 8 (PCH8; OMIM 614961), a neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects (Mochida et al., 2012).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo damaging missense variants in the CHMP1A gene were identifed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function variants in this gene were observed in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CHMP1A as an ASD candidate gene with a PTADA of 0.001528. Homozygous mutations in the CHMP1A gene are associated with pontocerebellar hypoplasia type 8 (PCH8; OMIM 614961), a neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects (Mochida et al., 2012).

Reports Added
[New Scoring Scheme]
7/1/2017
icon
3

Increased from to 3

Description

De novo damaging missense variants in the CHMP1A gene were identifed in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014). Rare inherited loss-of-function variants in this gene were observed in ASD probands from the Simons Simplex Collection (Krumm et al., 2015) and in a cohort of Chinese ASD probands (Guo et al., 2017). Transmission and De Novo Association (TADA) analysis of a combined cohort consisting of 536 Chinese ASD probands and 1457 Chinese controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium, in Guo et al., 2017 identified CHMP1A as an ASD candidate gene with a PTADA of 0.001528. Homozygous mutations in the CHMP1A gene are associated with pontocerebellar hypoplasia type 8 (PCH8; OMIM 614961), a neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects (Mochida et al., 2012).

Krishnan Probability Score

Score 0.49578320334712

Ranking 2805/25841 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 0.25203680941951

Ranking 6742/18225 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 0.49381771259856

Ranking 435/18665 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 -0.13211717116428

Ranking 13557/20870 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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