GNAI1

protein-coding

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

Gene summary

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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

MANE transcript

NM_002069.6

Inheritance

ClinVar variants

P:21U:116B:19

Top phenotype

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr7:79,768,028-80,226,181

External References & Databases

Ensembl (ENSG00000127955)

Transcript & Mutation Effects

hg38 • Region Span ~458.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859243

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859243

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Variants in GNAI1 were first reported in individuals with neurodevelopmental disorders between 2014 and 2017, when several large exome sequencing studies in autism or developmental disorders reported de novo GNAI1 variants in multiple probands without detailed clinical information (PMIDs: 25363760, 25363768, 28135719). GNAI1 encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. In 2021, Muir et al. described 16 unique GNAI1 variants in 24 individuals with neurodevelopmental disorders, some of whom had been described in previous publications (PMID: 33473207). Core clinical features include global developmental delay, intellectual disability, hypotonia, and epilepsy; some individuals also have autism and variable mild dysmorphic features. While the pLI and LOEUF scores for GNAI1 in gnomAD (v2.1.1) suggest intolerance to loss-of-function variation (0.91 and 0.38, respectively), most reported variants are missense or in-frame deletions, and functional studies have not been performed to assess the mechanism by which they impact gene function. However, many of the de novo missense variants identified in affected individuals are located at recurrent amino acid positions. This pattern of variation is characteristic of pathogenic missense variants in other G proteins, and suggests that the mechanism of pathogenicity could be antimorphic (or dominant-interfering). Homozygous knockout mice exhibit deficits in learning and memory (PMIDs: 14715142), but since most of the variants in humans are heterozygous missense/in-frame variants, this experimental evidence was not scored. In summary, there is definitive evidence to support the relationship between GNAI1 and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability/Autism Gene Curation Expert Panel on 3/17/2021.

neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859243

Submitter: Broad Center for Mendelian Genomics

neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859243

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 28135719; 33473207; 34819662

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GNAI1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 73

Inborn genetic diseasesTotal: 38

Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalitiesTotal: 34

GNAI1-related disorderTotal: 13

not specifiedTotal: 8

Neurodevelopmental disorderTotal: 3

GNAI1 associated Neurodevelopmental disorderTotal: 1

SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002069.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	9 clinvar	4 clinvar	16
missense	5 clinvar	16 clinvar	92 clinvar	6 clinvar		119
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift			11 clinvar			11
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	5	16	116	15	4	156

Highest pathogenic variant AF is 7.0146984e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002069.6	RefSeq	NP_002060.4	8	MANE Select
ENST00000649796.2	Ensembl	ENSP00000497260.1	8	MANE Select
NM_001256414.2	RefSeq	NP_001243343.1	7	Standard
ENST00000351004.8	Ensembl	ENSP00000343027.3	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

magnesium ion binding
G protein-coupled receptor binding
GTPase activity
protein binding
GTP binding

Cellular Component

nucleus
nucleolus
cytoplasm
lysosomal membrane
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000351004
Coding exons: 8
Length: 85448
Individuals with no LoFs: 125484
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125487
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.63	83	183	0.453	0.00000881	2358
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.0829

Intolerance Scores

LoFtool: 0.0437
RVIS EVS: -0.16
RVIS percentile EVS: 41.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.889

Gene Damage Prediction

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