Human Gene Module / Chromosome 20 / GNAS

GNASGNAS complex locus

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
6 / 6
Aliases
GNAS, NESP55 (OLD symbol),  XL,  AHO,  GSA,  GSP,  POH,  XL2,  GPSA,  NESP,  SCG6,  GNAS1,  PHP1A ,  PHP1B,  GNASXL,  NESP55,  C20orf45,  MGC33735,  XLalphas,  dJ309F20.1.1,  dJ806M20.3. 3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
20q13.32
Associated Disorders
-
Relevance to Autism

SNPs have been identified in the GNAS gene in a screening of autistic, OCD and ADHD patients (Kim et al., 2000). In addition, a rare mutation in the GNAS gene has been identified in an individual with ASD (Sanders et al., 2012).

Molecular Function

The encoded protein has GTPase activity.

Reports related to GNAS (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Wroe SF , et al. (2000) No -
2 Primary Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1. Kim SJ , et al. (2000) Yes OCD
3 Recent Recommendation Autosomal-dominant pseudohypoparathyroidism type Ib is caused by different microdeletions within or upstream of the GNAS locus. Jppner H , et al. (2006) No -
4 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
5 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
6 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
7 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
8 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.344G>A p.Trp115Ter stop_gained Familial - Simplex 28831199 Li J , et al. (2017)
c.475G>A p.Glu159Lys missense_variant De novo NA - 29158550 Popp B , et al. (2017)
c.*57_*80del - inframe_deletion Familial Maternal - 10860717 Kim SJ , et al. (2000)
c.772C>T p.Arg258Trp missense_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.510C>G p.Ala170%3D missense_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.2254G>A p.Ala752Thr missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
A1682G N/A intron_variant - - - 10860717 Kim SJ , et al. (2000)
C1649T N/A intron_variant - - - 10860717 Kim SJ , et al. (2000)
A797G - upstream_gene_variant - - - 10860717 Kim SJ , et al. (2000)
c.1031C>T p.(=) synonymous_variant - - - 10860717 Kim SJ , et al. (2000)
c.1142C>T p.(=) synonymous_variant - - - 10860717 Kim SJ , et al. (2000)
c.1235C>T p.(=) synonymous_variant - - - 10860717 Kim SJ , et al. (2000)
SFARI Gene score
3

Suggestive Evidence

SNPs have been identified in the GNAS gene in a screening of autistic, OCD and ADHD patients (Kim et al., 2000). De novo missense variants in GNAS have been identified in individuals with ASD (Sanders et al., 2012; Iossifov et al., 2014) and intellectual disability (Cherot et al., 2017; Popp et al., 2017). An inherited nonsense variant in GNAS was observed in a Chinese ASD proband from a simplex family in Li et al., 2017; no loss-of-function variants in this gene were observed in 1457 Chinese controls or in 1786 controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

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

SNPs have been identified in the GNAS gene in a screening of autistic, OCD and ADHD patients (Kim et al., 2000). De novo missense variants in GNAS have been identified in individuals with ASD (Sanders et al., 2012; Iossifov et al., 2014) and intellectual disability (Cherot et al., 2017; Popp et al., 2017). An inherited nonsense variant in GNAS was observed in a Chinese ASD proband from a simplex family in Li et al., 2017; no loss-of-function variants in this gene were observed in 1457 Chinese controls or in 1786 controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Reports Added
[New Scoring Scheme]
4/1/2018
icon
4.4

Increased from to 4.4

Description

4

Krishnan Probability Score

Score 0.49764854544633

Ranking 2352/25841 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 0.9995400816303

Ranking 921/18225 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 0.59395718478101

Ranking 689/18665 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 4

Ranking 309/461 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 -0.2572269278789

Ranking 16493/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
GNG5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5 Human Protein Binding 2787 P63218
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