GNAS

GNAS complex locus, the group of Granins|G protein subunits alpha, group s

Basic information

Region (hg38): 20:58839718-58911192

Previous symbols: [ "GNAS1" ]

Links

ENSG00000087460NCBI:2778OMIM:139320HGNC:4392Uniprot:O95467, P63092, P84996, Q5JWF2AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • pseudohypoparathyroidism type 1B (Definitive), mode of inheritance: Autosomal dominant inheritance with paternal imprinting
  • ACTH-independent macronodular adrenal hyperplasia 1 (Definitive), mode of inheritance: Somatic mosaicism
  • pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: AD
  • pseudohypoparathyroidism type 1A (Strong), mode of inheritance: AD
  • pseudohypoparathyroidism type 1B (Strong), mode of inheritance: AD
  • pseudohypoparathyroidism type 1C (Strong), mode of inheritance: AD
  • McCune-Albright syndrome (Strong), mode of inheritance: Unknown
  • progressive osseous heteroplasia (No Known Disease Relationship), mode of inheritance: AD
  • pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: AD
  • pseudopseudohypoparathyroidism (Moderate), mode of inheritance: AD
  • McCune-Albright syndrome (Definitive), mode of inheritance: Somatic mosaicism
  • progressive osseous heteroplasia (Supportive), mode of inheritance: AD
  • pseudohypoparathyroidism type 1A (Supportive), mode of inheritance: AD
  • pseudohypoparathyroidism type 1C (Supportive), mode of inheritance: AD
  • pseudopseudohypoparathyroidism (Supportive), mode of inheritance: AD
  • pseudohypoparathyroidism type 1B (Supportive), mode of inheritance: AD
  • McCune-Albright syndrome (Definitive), mode of inheritance: AD
  • pseudohypoparathyroidism type 1A (Definitive), mode of inheritance: Mitochondrial
  • pseudopseudohypoparathyroidism (Definitive), mode of inheritance: Mitochondrial
  • pseudohypoparathyroidism type 1C (Definitive), mode of inheritance: Mitochondrial
  • pseudohypoparathyroidism type 1B (Definitive), mode of inheritance: AD
  • McCune-Albright syndrome (Strong), mode of inheritance: AD
  • progressive osseous heteroplasia (Strong), mode of inheritance: AD
  • pseudohypoparathyroidism type 1A (Strong), mode of inheritance: AD
  • pseudopseudohypoparathyroidism (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Pseudohypoparathyroidism, type IA; Pseudohypoparathyroidism, type IB; Pseudohypoparathyroidism, type IC; Progressive osseous heteroplasia; McCune-Albright syndromeADEndocrine; Oncologic; RenalIn Pseudohypoparathyroidism, medical treatment (eg, with calcium and vitamin D therapy) of electrolyte abnormalities and related complications such as osteitis fibrosa cystica can be effective, and complications; Surveillance and early treatment of endocrinological manifestations (eg, hypothyroidism, hypogonadism) can be beneficial; In McCune-Albright syndrome, medical (eg, related to estrogen production, hyperthyroidism, growth hormone production) and surgical (eg, to treat adrenal pathology, hyperthyroidism) treatment of endocrinopathies may be beneficial, and surveillance and early and specific treatment for manifestations such as a number of types of neoplasms, including GH-producing tumors (eg, with long-acting octreotide, GHR antagonists) can be beneficial, as well as surveillance for and treatment of Cushing syndrome (some patients require adrenalectomy)Dermatologic; Endocrine; Musculoskeletal; Oncologic; Renal13005676; 5906056; 1083395; 198661; 219790; 431133; 6265935; 3126297; 2829196; 2273209; 2109828; 3093862; 2122458; 1955519; 1944469; 1400888; 1621772; 1424186; 1594625; 1346061; 8421479; 7980957; 8126048; 8126161; 7739708; 7671486; 9226216; 9506752; 0614538; 10356155; 10190480; 11073544; 10646121; 11067869; 11095461; 10998448; 11600516; 11406605; 11297617; 11583302; 11397863; 11029463; 12414879; 12024004; 12407707; 11788646; 11784876; 14561710; 12605446; 12727968; 12858292; 14557424; 12624854; 15001590; 15126527; 15711092; 16060910; 15537666; 16984995; 17405850; 17651445; 18553568; 18416659; 18397987; 20480732; 19858129; 21816789; 21488135; 21357941; 22640971
Mosaic variants have been described; PPHP occurs with paternal inheritance

ClinVar

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

  • not provided (72 variants)
  • Pseudohypoparathyroidism type I A (21 variants)
  • Pseudohypoparathyroidism (8 variants)
  • GNAS-related disorder (7 variants)
  • Inborn genetic diseases (7 variants)
  • 8 conditions (5 variants)
  • Pseudohypoparathyroidism type 1B (3 variants)
  • Pseudopseudohypoparathyroidism (3 variants)
  • McCune-Albright syndrome (3 variants)
  • Adrenal cortex carcinoma (2 variants)
  • Neoplasm of uterine cervix (2 variants)
  • Hepatocellular carcinoma (2 variants)
  • Pseudohypoparathyroidism type 1C (2 variants)
  • Lung adenocarcinoma (2 variants)
  • Pancreatic adenocarcinoma (2 variants)
  • Neoplasm of the large intestine (2 variants)
  • Sex cord-stromal tumor (2 variants)
  • Pituitary adenoma 3, multiple types (2 variants)
  • Gastric adenocarcinoma (2 variants)
  • Neoplasm (2 variants)
  • Squamous cell carcinoma of the head and neck (2 variants)
  • Progressive osseous heteroplasia (2 variants)
  • ACTH-independent macronodular adrenal hyperplasia 1 (2 variants)
  • Breast neoplasm (2 variants)
  • Malignant melanoma of skin (2 variants)
  • Hereditary spastic paraplegia 4 (1 variants)
  • Pseudohypoparathyroidism;Pseudopseudohypoparathyroidism (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GNAS 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
27
clinvar
125
clinvar
7
clinvar
159
missense
24
clinvar
26
clinvar
207
clinvar
23
clinvar
3
clinvar
283
nonsense
22
clinvar
4
clinvar
3
clinvar
29
start loss
4
clinvar
2
clinvar
2
clinvar
8
frameshift
32
clinvar
10
clinvar
12
clinvar
54
inframe indel
2
clinvar
3
clinvar
17
clinvar
2
clinvar
2
clinvar
26
splice donor/acceptor (+/-2bp)
14
clinvar
9
clinvar
23
splice region
1
2
13
21
37
non coding
3
clinvar
73
clinvar
39
clinvar
115
Total 98 54 269 225 51

Highest pathogenic variant AF is 0.0000131

Variants in GNAS

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

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

Position Type Phenotype Significance ClinVar
20-58839812-C-G Benign (Nov 16, 2018)1282105
20-58840055-A-G Benign (Oct 16, 2018)1280334
20-58840106-G-A GNAS-AS1-related condition Uncertain significance (Sep 15, 2024)3348393
20-58840109-G-A Likely pathogenic (Sep 16, 2018)562456
20-58840109-GGA-AAT GNAS-related disorder Uncertain significance (Feb 06, 2024)3357101
20-58840110-G-A Uncertain significance (Mar 01, 2023)2498888
20-58840112-T-C GNAS-related disorder Likely benign (Nov 12, 2021)3355872
20-58840113-C-G Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;Pseudohypoparathyroidism type I A • GNAS-related disorder Uncertain significance (Apr 08, 2022)2502231
20-58840113-C-T Pseudohypoparathyroidism type I A Uncertain significance (Oct 18, 2021)1684502
20-58840116-A-G not specified • GNAS-related disorder Uncertain significance (Oct 01, 2015)252708
20-58840129-A-C GNAS-related disorder Uncertain significance (Dec 12, 2023)3029991
20-58840133-G-A GNAS-related disorder Likely benign (Mar 09, 2021)3030466
20-58840140-C-T Pseudopseudohypoparathyroidism Likely pathogenic (-)3242103
20-58840147-G-A GNAS-related disorder Uncertain significance (Jun 19, 2024)3354491
20-58840147-G-T GNAS-related disorder Uncertain significance (Jun 13, 2024)3351166
20-58840150-A-G GNAS-related disorder Uncertain significance (Mar 29, 2023)2636584
20-58840162-A-AC GNAS-related disorder Uncertain significance (Oct 24, 2020)1319045
20-58840178-A-G GNAS-related disorder Uncertain significance (Oct 10, 2023)2633317
20-58840179-G-A GNAS-related disorder Uncertain significance (Oct 23, 2023)3352052
20-58840220-C-T GNAS-related disorder Likely benign (Apr 17, 2024)3349511
20-58840232-C-T GNAS-related disorder Likely benign (Jan 10, 2020)3051457
20-58840233-C-T GNAS-related disorder Uncertain significance (Nov 13, 2023)2628591
20-58840238-C-A GNAS-related disorder Likely benign (Nov 01, 2023)3351162
20-58840294-GCTTC-G Uncertain significance (Dec 29, 2022)2507307
20-58840312-A-T GNAS-related disorder Likely benign (Jun 22, 2022)3035607

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
GNASprotein_codingprotein_codingENST00000371100 1371475
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.6810.3191245751381246140.000157
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense2.654606510.7070.00004366674
Missense in Polyphen42196.770.213452112
Synonymous-0.1742752711.010.00002112131
Loss of Function4.59838.90.2060.00000209426

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001580.000156
Ashkenazi Jewish0.000.00
East Asian0.0002240.000223
Finnish0.000.00
European (Non-Finnish)0.0002560.000239
Middle Eastern0.0002240.000223
South Asian0.0001710.000131
Other0.0001660.000165

dbNSFP

Source: dbNSFP

Disease
DISEASE: ACTH-independent macronodular adrenal hyperplasia 1 (AIMAH1) [MIM:219080]: A rare adrenal defect characterized by multiple, bilateral, non-pigmented, benign, adrenocortical nodules. It results in excessive production of cortisol leading to ACTH-independent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:12727968}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A disorder characterized by end-organ resistance to parathyroid hormone, hypocalcemia and hyperphosphatemia. Patients affected with PHP1B lack developmental defects characteristic of Albright hereditary osteodystrophy, and typically show no other endocrine abnormalities besides resistance to PTH. {ECO:0000269|PubMed:11029463, ECO:0000269|PubMed:11067869, ECO:0000269|PubMed:11294659, ECO:0000269|PubMed:12858292, ECO:0000269|PubMed:14561710, ECO:0000269|PubMed:15592469, ECO:0000269|PubMed:15800843}. Note=The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed.; DISEASE: GNAS hyperfunction (GNASHYP) [MIM:139320]: This condition is characterized by increased trauma-related bleeding tendency, prolonged bleeding time, brachydactyly and mental retardation. Both the XLas isoforms and the ALEX protein are mutated which strongly reduces the interaction between them and this may allow unimpeded activation of the XLas isoforms. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
Inflammatory mediator regulation of TRP channels - Homo sapiens (human);Platelet activation - Homo sapiens (human);Cortisol synthesis and secretion - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Long-term depression - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Bile secretion - Homo sapiens (human);Vasopressin-regulated water reabsorption - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Amoebiasis - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human);Renin secretion - Homo sapiens (human);Vibrio cholerae infection - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Alcoholism - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Melanogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Selective Serotonin Reuptake Inhibitor Pathway, Pharmacodynamics;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Excitatory Neural Signalling Through 5-HTR 4 and Serotonin;Intracellular Signalling Through Adenosine Receptor A2b and Adenosine;Intracellular Signalling Through Adenosine Receptor A2a and Adenosine;Intracellular Signalling Through Prostacyclin Receptor and Prostacyclin;Corticotropin Activation of Cortisol Production;Excitatory Neural Signalling Through 5-HTR 7 and Serotonin ;Excitatory Neural Signalling Through 5-HTR 6 and Serotonin ;Vasopressin Regulation of Water Homeostasis;Intracellular Signalling Through PGD2 receptor and Prostaglandin D2;Intracellular Signalling Through LHCGR Receptor and Luteinizing Hormone/Choriogonadotropin;Intracellular Signalling Through FSH Receptor and Follicle Stimulating Hormone;Intracellular Signalling Through Histamine H2 Receptor and Histamine;Dopamine Activation of Neurological Reward System;Human Thyroid Stimulating Hormone (TSH) signaling pathway;Endothelin Pathways;Corticotropin-releasing hormone signaling pathway;Common Pathways Underlying Drug Addiction;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;Calcium Regulation in the Cardiac Cell;Estrogen signaling pathway;Serotonin Receptor 4-6-7 and NR3C Signaling;Signaling by GPCR;Signal Transduction;phospholipase c-epsilon pathway;gata3 participate in activating the th2 cytokine genes expression;transcription factor creb and its extracellular signals;regulation of ck1/cdk5 by type 1 glutamate receptors;corticosteroids and cardioprotection;cystic fibrosis transmembrane conductance regulator (cftr) and beta 2 adrenergic receptor (b2ar) pathway;ion channels and their functional role in vascular endothelium;ccr3 signaling in eosinophils;activation of csk by camp-dependent protein kinase inhibits signaling through the t cell receptor;chrebp regulation by carbohydrates and camp;signaling pathway from g-protein families;how progesterone initiates the oocyte maturation;attenuation of gpcr signaling;role of -arrestins in the activation and targeting of map kinases;activation of camp-dependent protein kinase pka;Glucagon signaling in metabolic regulation;GPCR Dopamine D1like receptor;GPCR Adenosine A2A receptor;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Metabolism;G alpha (s) signalling events;Transport of small molecules;Glucagon-like Peptide-1 (GLP1) regulates insulin secretion;Regulation of insulin secretion;roles of arrestin dependent recruitment of src kinases in gpcr signaling;CRH;regulation of spermatogenesis by crem;Glucagon-type ligand receptors;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Hedgehog ,off, state;GPCR signaling-G alpha s PKA and ERK;Signaling by Hedgehog;Hemostasis;-arrestins in gpcr desensitization;Rapid glucocorticoid signaling;G alpha (i) signalling events;G alpha (z) signalling events;PKA activation in glucagon signalling;GPCR signaling-G alpha i;Vasopressin regulates renal water homeostasis via Aquaporins;Aquaporin-mediated transport;TSH;Prostacyclin signalling through prostacyclin receptor;Integration of energy metabolism;Platelet homeostasis;GPCR downstream signalling;LPA4-mediated signaling events;Plasma membrane estrogen receptor signaling;Endothelins (Consensus)

Recessive Scores

pRec
0.800

Intolerance Scores

loftool
0.00834
rvis_EVS
-0.02
rvis_percentile_EVS
52.32

Haploinsufficiency Scores

pHI
0.484
hipred
Y
hipred_score
0.704
ghis
0.566

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
N
gene_indispensability_score
0.387

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Gnas
Phenotype
craniofacial phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); limbs/digits/tail phenotype; hearing/vestibular/ear 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); renal/urinary system phenotype; skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; neoplasm;

Gene ontology

Biological process
tissue homeostasis;endochondral ossification;energy reserve metabolic process;DNA methylation;adenylate cyclase-modulating G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;adenylate cyclase-activating dopamine receptor signaling pathway;embryonic hindlimb morphogenesis;multicellular organism growth;post-embryonic body morphogenesis;response to drug;positive regulation of catalytic activity;skin development;positive regulation of osteoblast differentiation;positive regulation of osteoclast differentiation;developmental growth;embryonic cranial skeleton morphogenesis;cartilage development;bone development;platelet aggregation;genetic imprinting;positive regulation of cold-induced thermogenesis;regulation of parathyroid hormone secretion
Cellular component
cytosol;heterotrimeric G-protein complex;membrane;apical plasma membrane;dendrite;extracellular exosome
Molecular function
G protein-coupled receptor binding;GTPase activity;insulin-like growth factor receptor binding;protein binding;GTP binding;adenylate cyclase activator activity;G-protein beta/gamma-subunit complex binding;beta-2 adrenergic receptor binding;D1 dopamine receptor binding;mu-type opioid receptor binding;ionotropic glutamate receptor binding;metal ion binding;corticotropin-releasing hormone receptor 1 binding