Human Gene Module / Chromosome 7 / GNAI1

GNAI1G protein subunit alpha i1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
3 / 6
Rare Variants / Common Variants
25 / 0
EAGLE Score
2.1
Limited Learn More
Aliases
GNAI1, Gi
Associated Syndromes
-
Chromosome Band
7q21.11
Associated Disorders
ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Two de novo missense variants that were predicted to be probably damaging (defined as MPC 2) were identified in the GNAI1 gene in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014), while a protein-truncating variant in this gene was observed in a case sample from the Danish iPSYCH study (Satterstrom et al., 2020). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified GNAI1 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05).

Molecular Function

Guanine nucleotide binding proteins are heterotrimeric signal-transducing molecules consisting of alpha, beta, and gamma subunits. The alpha subunit binds guanine nucleotide, can hydrolyze GTP, and can interact with other proteins. The protein encoded by this gene represents the alpha subunit of an inhibitory complex. The encoded protein is part of a complex that responds to beta-adrenergic signals by inhibiting adenylate cyclase.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GNAI1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent recommendation Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Recent recommendation - Muir AM et al. (2021) No ASD, epilepsy/seizures
5 Support - Lucie Sedlackova et al. (2024) No -
6 Support - Marketa Wayhelova et al. (2024) No -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.-14C>A - missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.14T>C p.Leu5Pro missense_variant Unknown - - 33473207 Muir AM et al. (2021)
c.118G>C p.Gly40Arg missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.118G>T p.Gly40Cys missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.134G>A p.Gly45Asp missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.143C>A p.Thr48Lys missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.143C>T p.Thr48Ile missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.155A>C p.Gln52Pro missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.262A>G p.Met88Val missense_variant Unknown - - 33473207 Muir AM et al. (2021)
c.518A>T p.Asp173Val missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.671G>A p.Cys224Tyr missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.809A>G p.Lys270Arg missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.810G>C p.Lys270Asn missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.976G>C p.Ala326Pro missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.995T>A p.Val332Glu missense_variant De novo - - 33473207 Muir AM et al. (2021)
c.222_224del p.Ser75del inframe_deletion De novo - - 33473207 Muir AM et al. (2021)
c.514_516del p.Gln172del inframe_deletion De novo - - 33473207 Muir AM et al. (2021)
c.118G>T p.Gly40Cys missense_variant Familial Maternal - 33473207 Muir AM et al. (2021)
c.676dup p.Ile226AsnfsTer20 frameshift_variant De novo - - 33473207 Muir AM et al. (2021)
c.548delG p.Gly183GlufsTer36 frameshift_variant Unknown - - 33473207 Muir AM et al. (2021)
c.611A>G p.Gln204Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.556_567del p.Glu186_Phe189del inframe_deletion De novo - - 33473207 Muir AM et al. (2021)
c.956T>C p.Ile319Thr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.514_516del p.Gln172del inframe_deletion De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.815A>G p.Asp272Gly missense_variant De novo - Multiplex (monozygotic twins) 38321498 Marketa Wayhelova et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
1

Increased from to 1

Krishnan Probability Score

Score 0.52584193644526

Ranking 1613/25841 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 0.91752824366579

Ranking 3060/18225 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 0.68683368274234

Ranking 1078/18665 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 0.36921750985084

Ranking 1797/20870 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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