EDN3

endothelin 3, the group of Endothelins

Basic information

Region (hg38): 20:59300442-59325992

Links

ENSG00000124205 ∙ NCBI:1908 ∙ OMIM:131242 ∙ HGNC:3178 ∙ Uniprot:P14138 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Waardenburg syndrome type 4B (Strong), mode of inheritance: AD
• Waardenburg syndrome type 4B (Strong), mode of inheritance: AR
• Waardenburg syndrome type 4B (Moderate), mode of inheritance: Semidominant
• Hirschsprung disease, susceptibility to, 4 (Moderate), mode of inheritance: AD
• Waardenburg-Shah syndrome (Supportive), mode of inheritance: AD
• Hirschsprung disease, susceptibility to, 4 (Limited), mode of inheritance: Unknown
• Waardenburg syndrome type 4B (Limited), mode of inheritance: AD
• Waardenburg syndrome type 4B (Limited), mode of inheritance: AD
• Waardenburg syndrome type 4B (Moderate), mode of inheritance: AR
• Waardenburg syndrome type 4B (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Waardenburg syndrome, type 4B; Central hypoventilation syndrome, congenital; Hirschsprung disease, susceptibility to, 4	AD/AR	Audiologic/Otolaryngologic; Gastrointestinal; Neurologic; Pulmonary	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In conditions that may involve Hirschsprung disease, recognition of potential GI anomalies (eg, aganglionosis) may allow prompt recognition and treatment; In Central hypoventilation syndrome, congenital, early recognition and interventions to support ventilation (as well as avoidance of exacerbating factors) can reduce morbidity and mortality	Audiologic/Otolaryngologic; Dermatologic; Gastrointestinal; Neurologic; Ophthalmologic; Pulmonary	8696331; 8630502; 8630503; 9279758; 9359047; 10231870; 11303518; 19764030; 20009762

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EDN3 gene.

• Hirschsprung disease, susceptibility to, 4 (66 variants)
• not provided (57 variants)
• not specified (14 variants)
• Inborn genetic diseases (12 variants)
• Hirschsprung Disease, Dominant (9 variants)
• Waardenburg syndrome (5 variants)
• Waardenburg syndrome type 4B (5 variants)
• Hirschsprung disease, susceptibility to, 4;Waardenburg syndrome type 4B (2 variants)
• Megacolon;Abnormal rectum morphology (1 variants)
• Congenital central hypoventilation (1 variants)
• Waardenburg syndrome type 4B;Hirschsprung disease, susceptibility to, 4 (1 variants)
• Sensorineural hearing loss disorder (1 variants)
• Aganglionic megacolon (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EDN3 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			2	10	1	13
missense		2	38	2		42
nonsense						0
start loss						0
frameshift			1	1		2
inframe indel			2	1		3
splice donor/acceptor (+/-2bp)						0
splice region			2	1		3
non coding			40	18	13	71
Total	0	2	83	32	14

Variants in EDN3

This is a list of pathogenic ClinVar variants found in the EDN3 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-59300454-T-A		Hirschsprung Disease, Dominant	Uncertain significance (Jun 14, 2016)
20-59300545-G-C		Hirschsprung Disease, Dominant	Uncertain significance (Jun 14, 2016)
20-59300565-G-A		Hirschsprung Disease, Dominant • not specified	Benign/Likely benign (Feb 01, 2024)
20-59300649-G-A		Hirschsprung disease, susceptibility to, 4	Uncertain significance (Jan 12, 2018)
20-59300693-C-T		Hirschsprung disease, susceptibility to, 4	Uncertain significance (Jan 13, 2018)
20-59300698-G-A		Hirschsprung disease, susceptibility to, 4	Uncertain significance (Jan 12, 2018)
20-59300727-G-A		Hirschsprung disease, susceptibility to, 4	Uncertain significance (Jan 13, 2018)
20-59300728-G-A		Hirschsprung disease, susceptibility to, 4	Uncertain significance (Jan 13, 2018)
20-59300736-T-A		Hirschsprung disease, susceptibility to, 4	Benign (Jan 13, 2018)
20-59300769-C-T		Hirschsprung disease, susceptibility to, 4	Likely benign (Jan 12, 2018)
20-59300794-C-A			Uncertain significance (Sep 08, 2021)
20-59300823-G-C			Uncertain significance (Aug 04, 2023)
20-59300836-T-G		not specified	Likely benign (Sep 06, 2017)
20-59300838-T-A		Inborn genetic diseases	Uncertain significance (May 17, 2023)
20-59300855-T-G		Hirschsprung disease, susceptibility to, 4 • Hirschsprung disease, susceptibility to, 4;Waardenburg syndrome type 4B	Uncertain significance (Feb 15, 2022)
20-59300860-C-T			Likely benign (Aug 16, 2022)
20-59300861-G-A		Hirschsprung disease, susceptibility to, 4 • not specified	Conflicting classifications of pathogenicity (Feb 01, 2024)
20-59300871-G-T			Likely benign (Sep 14, 2021)
20-59300989-C-T			Benign (Dec 17, 2018)
20-59301100-G-A			Benign (Nov 11, 2018)
20-59301185-G-T			Benign (Nov 11, 2018)
20-59301494-G-A			Uncertain significance (Mar 02, 2023)
20-59301498-AGAGACTGTGGCTGGCCCTGGCGAG-A		EDN3-related disorder	Likely benign (Nov 24, 2023)
20-59301498-A-AGAGACTGTGGCTGGCCCTGGCGAG		Megacolon;Abnormal rectum morphology	Uncertain significance (Oct 08, 2022)
20-59301519-C-T			Uncertain significance (Aug 14, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EDN3	protein_coding	protein_coding	ENST00000337938	5	25566

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0246	0.922	125666	0	5	125671	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.939	168	137	1.23	0.00000874	1519
Missense in Polyphen		33	34.757	0.94946		366
Synonymous	0.118	57	58.1	0.980	0.00000390	492
Loss of Function	1.65	4	9.50	0.421	4.99e-7	107

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.000101	0.0000992
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.00000895	0.00000880
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Endothelins are endothelium-derived vasoconstrictor peptides.
• Disease: DISEASE: Congenital central hypoventilation syndrome (CCHS) [MIM:209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. {ECO:0000269|PubMed:8696331}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Waardenburg syndrome 4B (WS4B) [MIM:613265]: A disorder characterized by the association of Waardenburg features (depigmentation and deafness) with the absence of enteric ganglia in the distal part of the intestine (Hirschsprung disease). {ECO:0000269|PubMed:11303518, ECO:0000269|PubMed:12189494, ECO:0000269|PubMed:8630503}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signaling by GPCR;Signal Transduction;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;G alpha (q) signalling events;GPCR downstream signalling;Endothelins (Consensus)

Recessive Scores

• pRec: 0.370

Intolerance Scores

• loftool: 0.0739
• rvis_EVS: -0.36
• rvis_percentile_EVS: 28.93

Haploinsufficiency Scores

• pHI: 0.372
• hipred: N
• hipred_score: 0.450
• ghis: 0.443

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0610

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Edn3
• 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); embryo phenotype; digestive/alimentary 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); pigmentation 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: edn3b
• Affected structure: melanocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased pigmentation

Gene ontology

• Biological process: neural crest cell migration;positive regulation of leukocyte chemotaxis;regulation of systemic arterial blood pressure by endothelin;cellular calcium ion homeostasis;signal transduction;cell surface receptor signaling pathway;G protein-coupled receptor signaling pathway;cell-cell signaling;multicellular organism development;blood circulation;positive regulation of cell population proliferation;positive regulation of heart rate;regulation of gene expression;regulation of signaling receptor activity;cellular magnesium ion homeostasis;artery smooth muscle contraction;vein smooth muscle contraction;regulation of vasoconstriction;peptide hormone secretion;neuron differentiation;melanocyte differentiation;neutrophil chemotaxis;vasoconstriction;positive regulation of MAP kinase activity;positive regulation of cell differentiation;positive regulation of mitotic nuclear division;positive regulation of hormone secretion;inositol phosphate-mediated signaling;regulation of developmental pigmentation;positive regulation of potassium ion transmembrane transport
• Cellular component: extracellular region;extracellular space;cell
• Molecular function: signaling receptor binding;hormone activity;endothelin B receptor binding