GNAI1

G protein subunit alpha i1, the group of G protein subunits alpha, group i

Basic information

Region (hg38): 7:79768028-80226181

Links

ENSG00000127955 ∙ NCBI:2770 ∙ OMIM:139310 ∙ HGNC:4384 ∙ Uniprot:P63096 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (Strong), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (Strong), mode of inheritance: AD
• neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal; Neurologic	28135719; 33473207; 34819662

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GNAI1 gene.

• Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (2 variants)
• not provided (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNAI1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				1	2	3
missense	2	11	40	3		56
nonsense			2			2
start loss			1			1
frameshift			4			4
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region				1		1
non coding			2		1	3
Total	2	11	50	4	3

Variants in GNAI1

This is a list of pathogenic ClinVar variants found in the GNAI1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-80135159-C-T		not specified	Uncertain significance (Apr 01, 2024)
7-80135161-A-G		Developmental disorder	Uncertain significance (Feb 07, 2024)
7-80135174-T-C			Uncertain significance (Dec 15, 2022)
7-80135179-G-A		Inborn genetic diseases	Likely benign (May 24, 2023)
7-80135197-G-C			Uncertain significance (Feb 23, 2022)
7-80135224-A-T		not specified	Uncertain significance (Jun 07, 2024)
7-80135225-ACCT-A		Neurodevelopmental abnormality	Likely pathogenic (Jun 04, 2020)
7-80135244-G-C		Inborn genetic diseases	Uncertain significance (Apr 01, 2024)
7-80135250-G-A		GNAI1-related disorder	Likely benign (Oct 28, 2019)
7-80135278-G-C			Pathogenic (May 25, 2021)
7-80135278-G-T		Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Likely pathogenic (May 04, 2022)
7-80135283-G-A		Inborn genetic diseases	Likely benign (Jul 20, 2021)
7-80188962-T-G		Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Likely pathogenic (Sep 22, 2024)
7-80188965-G-T			Uncertain significance (Mar 30, 2023)
7-80188966-G-A		Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Likely pathogenic (Apr 17, 2023)
7-80188966-G-T		GNAI1-related disorder	Uncertain significance (Jan 27, 2022)
7-80188974-A-C		Seizure	Likely pathogenic (-)
7-80188975-C-A		Neurodevelopmental disorder • Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Likely pathogenic (Oct 21, 2019)
7-80188984-A-G			Uncertain significance (Apr 19, 2024)
7-80188987-A-C			Likely pathogenic (Oct 23, 2020)
7-80189085-A-G		GNAI1-related disorder	Likely benign (Feb 28, 2019)
7-80189095-T-C			Uncertain significance (Mar 21, 2024)
7-80189097-C-G			Uncertain significance (May 26, 2024)
7-80189098-A-C		Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	not provided (-)
7-80189098-A-G		Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities	Likely pathogenic (Mar 29, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GNAI1	protein_coding	protein_coding	ENST00000351004	8	85448

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.911	0.0887	125484	0	3	125487	0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.63	83	183	0.453	0.00000881	2358
Missense in Polyphen		23	71.9	0.31989		915
Synonymous	-2.05	80	59.9	1.34	0.00000281	616
Loss of Function	3.32	2	16.6	0.120	8.57e-7	218

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000272	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:8774883, PubMed:18434541). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (By similarity). The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. Required for normal cytokinesis during mitosis (PubMed:17635935). Required for cortical dynein-dynactin complex recruitment during metaphase (PubMed:22327364). {ECO:0000250|UniProtKB:P10824, ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:18434541, ECO:0000269|PubMed:22327364, ECO:0000269|PubMed:8774883}.
• Pathway: Platelet activation - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Pertussis - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Long-term depression - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Chemokine signaling pathway - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Axon guidance - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Renin secretion - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Toxoplasmosis - Homo sapiens (human);Sphingolipid signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics;Leukocyte transendothelial migration - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Nicotine Activity on Dopaminergic Neurons;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Endothelin Pathways;Corticotropin-releasing hormone signaling pathway;Signal Transduction of S1P Receptor;Common Pathways Underlying Drug Addiction;G Protein Signaling Pathways;Cell-type Dependent Selectivity of CCK2R Signaling;Chemokine signaling pathway;Calcium Regulation in the Cardiac Cell;Serotonin HTR1 Group and FOS Pathway;Signaling by GPCR;Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding;Signal Transduction;bioactive peptide induced signaling pathway;aspirin blocks signaling pathway involved in platelet activation;cxcr4 signaling pathway;phospholipids as signalling intermediaries;signaling pathway from g-protein families;thrombin signaling and protease-activated receptors;how progesterone initiates the oocyte maturation;Metabolism of proteins;GPCR signaling-G alpha q;ADP signalling through P2Y purinoceptor 12;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Chaperonin-mediated protein folding;Metabolism;G alpha (s) signalling events;Adrenaline,noradrenaline inhibits insulin secretion;Regulation of insulin secretion;Signal amplification;Neuronal System;CRH;GPCR signaling-G alpha s Epac and ERK;Platelet activation, signaling and aggregation;GPCR signaling-G alpha s PKA and ERK;S1P5 pathway;SHP2 signaling;Adenylate cyclase inhibitory pathway;Inhibition of adenylate cyclase pathway;Activation of GABAB receptors;CXCR4-mediated signaling events;Hemostasis;Protein folding;G-protein activation;GABA B receptor activation;PLC beta mediated events;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses;G-protein mediated events;Opioid Signalling;G alpha (i) signalling events;G alpha (z) signalling events;GPCR signaling-G alpha i;TSH;Integration of energy metabolism;GPCR downstream signalling;PAR1-mediated thrombin signaling events;LPA receptor mediated events;S1P1 pathway;S1P3 pathway;CXCR3-mediated signaling events;S1P4 pathway;Plasma membrane estrogen receptor signaling;Nongenotropic Androgen signaling;Hedgehog signaling events mediated by Gli proteins;Sphingosine 1-phosphate (S1P) pathway;Endothelins;S1P2 pathway (Consensus)

Recessive Scores

• pRec: 0.0829

Intolerance Scores

• loftool: 0.0437
• rvis_EVS: -0.16
• rvis_percentile_EVS: 41.64

Haploinsufficiency Scores

• pHI: 0.454
• hipred: Y
• hipred_score: 0.786
• ghis: 0.457

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.889

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gnai1
• Phenotype: homeostasis/metabolism phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; immune system phenotype

Gene ontology

• Biological process: protein folding;cell cycle;G protein-coupled receptor signaling pathway;adenylate cyclase-modulating G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;response to peptide hormone;regulation of cAMP-mediated signaling;cell division;regulation of mitotic spindle organization;cellular response to forskolin;positive regulation of protein localization to cell cortex
• Cellular component: nucleus;nucleolus;cytoplasm;lysosomal membrane;centrosome;heterotrimeric G-protein complex;plasma membrane;midbody;extracellular exosome;cell cortex region
• Molecular function: magnesium ion binding;G protein-coupled receptor binding;GTPase activity;protein binding;GTP binding;GDP binding;G-protein beta/gamma-subunit complex binding;G protein-coupled serotonin receptor binding