NOS3

nitric oxide synthase 3

Basic information

Region (hg38): 7:150991016-151014588

Links

ENSG00000164867 ∙ NCBI:4846 ∙ OMIM:163729 ∙ HGNC:7876 ∙ Uniprot:P29474 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NOS3 gene.

• not provided (87 variants)
• Inborn genetic diseases (39 variants)
• not specified (7 variants)
• Premature ovarian failure (2 variants)
• Essential hypertension (1 variants)
• Alzheimer disease type 1 (1 variants)
• Alzheimer disease (1 variants)
• Alzheimer disease, late-onset, susceptibility to (1 variants)
• Ischemic stroke (1 variants)
• Hypertension resistant to conventional therapy (1 variants)
• Alzheimer disease type 1;Ischemic stroke;Preeclampsia/eclampsia 1;Essential hypertension, genetic (1 variants)
• Preeclampsia/eclampsia 1;Ischemic stroke;Essential hypertension, genetic;Alzheimer disease type 1 (1 variants)
• Ischemic heart disease, susceptibility to (1 variants)
• Hypertension, pregnancy-induced, susceptibility to (1 variants)
• NOS3-related condition (1 variants)
• Metabolic syndrome, susceptibility to (1 variants)
• Coronary artery spasm 1, susceptibility to (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOS3 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				20	12	32
missense		2	44	7	9	62
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				4	1	5
non coding				5	29	34
Total	0	2	44	32	50

Highest pathogenic variant AF is 0.00000657

Variants in NOS3

This is a list of pathogenic ClinVar variants found in the NOS3 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-150992991-C-T		Metabolic syndrome, susceptibility to	protective (Jun 01, 2017)
7-150992991-C-C		Coronary artery spasm 1, susceptibility to	risk factor (Jun 08, 1999)
7-150993827-C-T			Likely benign (Jul 18, 2018)
7-150993838-G-A		not specified	Uncertain significance (Jan 22, 2024)
7-150993881-C-T			Likely benign (Dec 31, 2019)
7-150993924-G-T		not specified	Uncertain significance (Oct 05, 2023)
7-150993949-C-T		not specified	Uncertain significance (Jun 16, 2023)
7-150995216-C-T		Premature ovarian failure	Likely pathogenic (Mar 02, 2020)
7-150995269-G-C		not specified	Uncertain significance (Feb 28, 2023)
7-150995271-T-C		not specified	Uncertain significance (Nov 18, 2022)
7-150995323-G-A			Likely benign (Nov 05, 2018)
7-150995356-G-A			Benign (May 13, 2021)
7-150996342-C-G			Benign (May 22, 2021)
7-150996397-G-T			Likely benign (Jun 05, 2018)
7-150996404-G-A		not specified	Uncertain significance (Oct 26, 2022)
7-150996417-C-T		Essential hypertension	Uncertain significance (Aug 14, 2019)
7-150996425-C-T		NOS3-related disorder	Uncertain significance (Sep 18, 2023)
7-150996468-G-A			Benign (May 04, 2021)
7-150996501-T-C		not specified	Uncertain significance (May 17, 2023)
7-150996504-T-G		not specified	Uncertain significance (Apr 12, 2022)
7-150996510-A-T		not specified	Uncertain significance (Mar 12, 2024)
7-150996515-C-T		not specified	Uncertain significance (Oct 26, 2021)
7-150996516-G-A		NOS3-related disorder	Benign/Likely benign (Jun 01, 2020)
7-150996808-C-G		Alzheimer disease type 1;Ischemic stroke;Preeclampsia/eclampsia 1;Essential hypertension, genetic	Benign/Likely benign (Oct 08, 2021)
7-150996848-G-A		Premature ovarian failure	Likely pathogenic (Mar 02, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NOS3	protein_coding	protein_coding	ENST00000297494	26	23594

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.72e-7	1.00	125676	0	72	125748	0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.04	610	769	0.793	0.0000499	7651
Missense in Polyphen		199	306.28	0.64973		3063
Synonymous	0.505	323	335	0.965	0.0000223	2514
Loss of Function	4.82	23	65.0	0.354	0.00000348	637

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000687	0.000660
Ashkenazi Jewish	0.0000997	0.0000992
East Asian	0.000344	0.000326
Finnish	0.000246	0.000231
European (Non-Finnish)	0.000330	0.000316
Middle Eastern	0.000344	0.000326
South Asian	0.000234	0.000229
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
• Disease: DISEASE: Note=Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm. {ECO:0000269|PubMed:11740345, ECO:0000269|PubMed:9737779}.
• Pathway: Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics;PI3K-Akt signaling pathway - Homo sapiens (human);Platelet activation - Homo sapiens (human);Relaxin signaling pathway - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Arginine and proline metabolism - Homo sapiens (human);VEGF signaling pathway - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Doxorubicin Pathway (Cancer Cell), Pharmacodynamics;AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics;Calcium signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Doxorubicin Pathway, Pharmacokinetics;Sphingolipid signaling pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Arginine biosynthesis - Homo sapiens (human);ACE Inhibitor Pathway, Pharmacodynamics;VEGF Signaling Pathway;Doxorubicin Metabolism Pathway;Angiogenesis;Angiogenesis overview;Effects of Nitric Oxide;Leptin signaling pathway;Endothelin Pathways;AGE-RAGE pathway;Corticotropin-releasing hormone signaling pathway;JAK-STAT;Myometrial Relaxation and Contraction Pathways;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;VEGFA-VEGFR2 Signaling Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;NO-cGMP-PKG mediated Neuroprotection;PI3K-Akt Signaling Pathway;EGF-EGFR Signaling Pathway;ACE Inhibitor Pathway;Signal Transduction;hypoxia-inducible factor in the cardivascular system;corticosteroids and cardioprotection;ion channels and their functional role in vascular endothelium;vegf hypoxia and angiogenesis;VEGFA-VEGFR2 Pathway;Metabolism of nitric oxide;ROS, RNS production in phagocytes;eNOS activation;NOSIP mediated eNOS trafficking;NOSTRIN mediated eNOS trafficking;eNOS activation and regulation;Innate Immune System;Immune System;Metabolism;Ghrelin;citrulline-nitric oxide cycle;actions of nitric oxide in the heart;Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation;Metabolism of cofactors;Metabolism of vitamins and cofactors;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;EGFR1;SHP2 signaling;Arginine Proline metabolism;Hemostasis;Thromboxane A2 receptor signaling;Signaling by VEGF;Angiopoietin receptor Tie2-mediated signaling;Leptin;Signaling by Receptor Tyrosine Kinases;Nitric oxide stimulates guanylate cyclase;Platelet homeostasis;PAR1-mediated thrombin signaling events;Plasma membrane estrogen receptor signaling;Validated transcriptional targets of AP1 family members Fra1 and Fra2;Signaling events mediated by VEGFR1 and VEGFR2;VEGFR1 specific signals;VEGFR2 mediated vascular permeability (Consensus)

Recessive Scores

• pRec: 0.808

Intolerance Scores

• loftool: 0.817
• rvis_EVS: -1.1
• rvis_percentile_EVS: 6.97

Haploinsufficiency Scores

• pHI: 0.240
• hipred: Y
• hipred_score: 0.637
• ghis: 0.479

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.793

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nos3
• 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; 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); 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); reproductive system phenotype; vision/eye phenotype; digestive/alimentary phenotype; limbs/digits/tail 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; homeostasis/metabolism phenotype; cellular 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; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: angiogenesis;ovulation from ovarian follicle;in utero embryonic development;blood vessel remodeling;regulation of sodium ion transport;regulation of the force of heart contraction by chemical signal;regulation of systemic arterial blood pressure by endothelin;aortic valve morphogenesis;pulmonary valve morphogenesis;endocardial cushion morphogenesis;arginine catabolic process;nitric oxide biosynthetic process;mitochondrion organization;nitric oxide mediated signal transduction;regulation of blood pressure;negative regulation of cell population proliferation;response to heat;response to hormone;negative regulation of platelet activation;positive regulation of gene expression;negative regulation of muscle hyperplasia;smooth muscle hyperplasia;removal of superoxide radicals;lung development;positive regulation of guanylate cyclase activity;lipopolysaccharide-mediated signaling pathway;response to lipopolysaccharide;response to fluid shear stress;vasodilation;negative regulation of potassium ion transport;positive regulation of blood vessel endothelial cell migration;endothelial cell migration;cell redox homeostasis;positive regulation of angiogenesis;negative regulation of blood pressure;homeostasis of number of cells within a tissue;regulation of blood vessel size;regulation of nitric-oxide synthase activity;cofactor metabolic process;negative regulation of hydrolase activity;negative regulation of calcium ion transport;oxidation-reduction process;ventricular septum morphogenesis;negative regulation of biomineral tissue development;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
• Cellular component: Golgi membrane;nucleus;cytoplasm;Golgi apparatus;cytosol;cytoskeleton;plasma membrane;caveola;vesicle membrane;endocytic vesicle membrane
• Molecular function: actin monomer binding;NADPH-hemoprotein reductase activity;nitric-oxide synthase activity;protein binding;calmodulin binding;FMN binding;oxidoreductase activity;heme binding;tetrahydrobiopterin binding;arginine binding;cadmium ion binding;flavin adenine dinucleotide binding;NADP binding;scaffold protein binding