GNAI3

G protein subunit alpha i3, the group of G protein subunits alpha, group i

Basic information

Region (hg38): 1:109548615-109600195

Links

ENSG00000065135 ∙ NCBI:2773 ∙ OMIM:139370 ∙ HGNC:4387 ∙ Uniprot:P08754 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• auriculocondylar syndrome 1 (Definitive), mode of inheritance: AD
• auriculocondylar syndrome 1 (Moderate), mode of inheritance: AD
• auriculocondylar syndrome (Supportive), mode of inheritance: AD
• auriculocondylar syndrome 1 (Moderate), mode of inheritance: AD
• auriculocondylar syndrome 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Auriculocondylar syndrome 1	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	22560091; 23315542

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GNAI3 gene.

• Auriculocondylar syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNAI3 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				8	2	10
missense	1	3	18	4		26
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region				1	1	2
non coding				1	6	7
Total	1	3	20	13	8

Variants in GNAI3

This is a list of pathogenic ClinVar variants found in the GNAI3 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-109548649-C-T			Benign (May 12, 2021)
1-109548660-C-T			Benign (May 12, 2021)
1-109548749-A-G		Inborn genetic diseases	Uncertain significance (Dec 06, 2021)
1-109548782-G-A		GNAI3-related disorder	Likely benign (Aug 09, 2019)
1-109548792-G-C		GNAI3-related disorder	Likely benign (Apr 12, 2022)
1-109548796-G-A			Uncertain significance (Oct 19, 2023)
1-109548799-G-A		Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
1-109548825-G-A			Benign (Jan 22, 2024)
1-109548838-G-C		Auriculocondylar syndrome 1	Pathogenic/Likely pathogenic (Dec 18, 2023)
1-109548839-G-C			Uncertain significance (May 10, 2021)
1-109573737-G-T			Likely pathogenic (Feb 22, 2023)
1-109573754-A-G		Auriculocondylar syndrome 1	Likely pathogenic (Jul 01, 2023)
1-109573758-G-A		Auriculocondylar syndrome 1	Pathogenic/Likely pathogenic (Jul 17, 2024)
1-109573759-C-A		Auriculocondylar syndrome 1	Pathogenic (Mar 01, 2013)
1-109573761-C-A			Likely pathogenic (Apr 21, 2017)
1-109573763-A-G		Auriculocondylar syndrome 1	Uncertain significance (Mar 08, 2021)
1-109573764-T-C		Auriculocondylar syndrome 1	Uncertain significance (Jan 03, 2022)
1-109573775-A-G			Uncertain significance (Jan 02, 2024)
1-109573797-G-A			Likely benign (Mar 24, 2023)
1-109573889-T-C			Benign (Jul 07, 2023)
1-109573903-C-T		not specified	Uncertain significance (Feb 06, 2024)
1-109573957-A-G		Inborn genetic diseases	Uncertain significance (Jun 17, 2024)
1-109573958-G-A			Uncertain significance (Dec 06, 2023)
1-109573984-A-G		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
1-109574003-G-A		GNAI3-related disorder	Likely benign (Dec 31, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GNAI3	protein_coding	protein_coding	ENST00000369851	8	45743

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0383	0.960	125728	0	18	125746	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.79	122	192	0.636	0.00000938	2347
Missense in Polyphen		38	75.49	0.50338		956
Synonymous	0.335	64	67.5	0.948	0.00000322	642
Loss of Function	2.82	6	19.4	0.309	0.00000108	238

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)	0.000124	0.000123
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Heterotrimeric 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, PubMed:19478087). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19478087). Stimulates the activity of receptor-regulated K(+) channels (PubMed:2535845). The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division (PubMed:17635935). {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:18434541, ECO:0000269|PubMed:2535845, ECO:0000269|PubMed:8774883}.
• Disease: DISEASE: Auriculocondylar syndrome 1 (ARCND1) [MIM:602483]: An autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. {ECO:0000269|PubMed:22560091}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• 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);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;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Signal Transduction of S1P Receptor;Human Complement System;G Protein Signaling Pathways;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;Metabolism of proteins;ADP signalling through P2Y purinoceptor 12;Chaperonin-mediated protein folding;G alpha (s) signalling events;Signal amplification;Neuronal System;Platelet activation, signaling and aggregation;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;TSH;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: 0.156

Intolerance Scores

• loftool: 0.449
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.42

Haploinsufficiency Scores

• pHI: 0.631
• hipred: Y
• hipred_score: 0.756
• ghis: 0.673

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.903

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gnai3
• Phenotype: immune system phenotype; skeleton phenotype; hematopoietic system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: protein folding;vesicle fusion;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;negative regulation of adenylate cyclase activity;dopamine receptor signaling pathway;brain development;positive regulation of macroautophagy;positive regulation of superoxide anion generation;positive regulation of NAD(P)H oxidase activity;GTP metabolic process;cell division;positive regulation of vascular smooth muscle cell proliferation;negative regulation of apoptotic signaling pathway
• Cellular component: Golgi membrane;nucleus;nucleolus;cytoplasm;lysosomal membrane;endoplasmic reticulum membrane;centrosome;heterotrimeric G-protein complex;plasma membrane;membrane;midbody;zymogen granule;membrane raft;extracellular exosome
• Molecular function: G protein-coupled receptor binding;GTPase activity;protein binding;GTP binding;GDP binding;protein domain specific binding;G-protein beta/gamma-subunit complex binding;G protein-coupled serotonin receptor binding;GTPase activating protein binding;metal ion binding