Human Gene Module / Chromosome 20 / GNAS

GNASGNAS complex locus

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 9
Rare Variants / Common Variants
8 / 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
-
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GNAS (9 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 2 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 -
9 Support - Zhou X et al. (2022) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2002C>G p.Leu668Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.475G>A p.Glu159Lys missense_variant De novo - - 29158550 Popp B , et al. (2017)
c.344G>A p.Trp115Ter stop_gained Familial - Simplex 28831199 Li J , et al. (2017)
c.772C>T p.Arg258Trp missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.*57_*80del - inframe_deletion Familial Maternal - 10860717 Kim SJ , et al. (2000)
c.1744G>A p.Asp582Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.510C>G p.Ala170= missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.2254G>A p.Ala752Thr missense_variant De novo - 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
2

Strong Candidate

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: 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

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.

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]
7/1/2018
icon
4

Increased from to 4

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.

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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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
Submit New Gene

Report an Error