NOS3

protein-coding

nitric oxide synthase 3

Gene summary

Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

MANE transcript

NM_000603.5

Inheritance

—

ClinVar variants

P:2U:181B:60

Top phenotype

NOS3-related disorder

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr7:150,991,017-151,014,588

External References & Databases

Ensembl (ENSG00000164867)

Transcript & Mutation Effects

hg38 • Region Span ~23.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NOS3 variants in ClinVar

11 Conditions Cataloged

not specifiedTotal: 160

not providedTotal: 79

NOS3-related disorderTotal: 28

Alzheimer disease type 1Total: 5

Essential hypertension, geneticTotal: 2

Premature ovarian failureTotal: 2

Ischemic strokeTotal: 2

Preeclampsia/eclampsia 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000603.5. 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			8 clinvar	29 clinvar	8 clinvar	45
missense		2 clinvar	170 clinvar	17 clinvar	6 clinvar	195
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	2	181	46	14	243

Highest pathogenic variant AF is 0.0000062267354

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000603.5	RefSeq	NP_000594.2	26	MANE Select
ENST00000297494.8	Ensembl	ENSP00000297494.3	26	MANE Select
NM_001160109.2	RefSeq	NP_001153581.1	14	Standard
NM_001160110.1	RefSeq	NP_001153582.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

angiogenesis
ovulation from ovarian follicle
in utero embryonic development
blood vessel remodeling
regulation of sodium ion transport

Molecular Function

actin monomer binding
NADPH-hemoprotein reductase activity
nitric-oxide synthase activity
protein binding
calmodulin binding

Cellular Component

Golgi membrane
nucleus
cytoplasm
Golgi apparatus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000297494
Coding exons: 26
Length: 23594
Individuals with no LoFs: 125676
Homozygous LoFs: 0
Heterozygous LoFs: 72
Defined: 125748
p: 0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.04	610	769	0.793	0.0000499	7651
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00034	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00034	0.00033	rare
Finnish	0.00025	0.00023	rare
European (Non-Finnish)	0.00033	0.00032	rare
South Asian	0.00023	0.00023	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.808

Intolerance Scores

LoFtool: 0.817
RVIS EVS: -1.1
RVIS percentile EVS: 6.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.793

Gene Damage Prediction

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