NODAL

nodal growth differentiation factor, the group of Transforming growth factor beta superfamily

Basic information

Region (hg38): 10:70431935-70447951

Links

ENSG00000156574 ∙ NCBI:4838 ∙ OMIM:601265 ∙ HGNC:7865 ∙ Uniprot:Q96S42 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• situs inversus (Disputed Evidence), mode of inheritance: AD
• situs inversus (Definitive), mode of inheritance: AD
• situs inversus (Supportive), mode of inheritance: AD
• heterotaxy, visceral, 5, autosomal (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Heterotaxy, visceral, 5, autosomal	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management; Cardiac transplantation has been described	Cardiovascular; Gastrointestinal; Pulmonary; Renal	19064609
The condition can involve multiple congenital anomalies; Cardiac transplantation has been described

ClinVar

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

• Heterotaxy, visceral, 5, autosomal (101 variants)
• Holoprosencephaly sequence (48 variants)
• not provided (30 variants)
• Inborn genetic diseases (12 variants)
• not specified (6 variants)
• Visceral heterotaxy (3 variants)
• NODAL-related condition (3 variants)
• Heart, malformation of (2 variants)
• Situs inversus (2 variants)
• NODAL-Related Disorders (2 variants)
• Congenitally corrected transposition of the great arteries (1 variants)
• Wolff-Parkinson-White pattern (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NODAL 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			4	18	4	26
missense	1	1	48	6	2	58
nonsense	2	1				3
start loss						0
frameshift	2	1	2			5
inframe indel			2			2
splice donor/acceptor (+/-2bp)		2	1			3
splice region			1			1
non coding			15	4	11	30
Total	5	5	72	28	17

Variants in NODAL

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

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

Position	Type	Phenotype	Significance	ClinVar
10-70432049-G-A		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432050-C-T		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Benign (Jan 12, 2018)
10-70432100-C-G		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
10-70432107-A-C		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432116-C-G		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432188-C-CT		Visceral heterotaxy • Holoprosencephaly sequence	Uncertain significance (Jun 14, 2016)
10-70432196-A-G		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Benign (Jan 12, 2018)
10-70432207-T-C		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
10-70432214-C-G		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Benign (Jan 13, 2018)
10-70432258-C-T		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
10-70432259-G-A		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Likely benign (Jan 12, 2018)
10-70432260-G-A		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
10-70432456-C-T		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432457-G-A		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Benign (Jan 13, 2018)
10-70432532-A-G		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Benign (Jan 12, 2018)
10-70432576-T-C		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432580-C-T		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Benign (Jan 12, 2018)
10-70432607-T-G		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 12, 2018)
10-70432608-C-T		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Apr 27, 2017)
10-70432811-T-G		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Uncertain significance (Jan 13, 2018)
10-70432815-G-T		Holoprosencephaly sequence • Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 13, 2018)
10-70432874-T-A		Heterotaxy, visceral, 5, autosomal • Holoprosencephaly sequence	Benign/Likely benign (Nov 09, 2019)
10-70432941-G-A		Heterotaxy, visceral, 5, autosomal	Uncertain significance (Jan 18, 2024)
10-70432947-C-T			Uncertain significance (Jun 12, 2022)
10-70432959-C-A		congenital heart defects	Uncertain significance (Mar 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NODAL	protein_coding	protein_coding	ENST00000287139	3	15637

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.970	0.0297	125742	0	6	125748	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.971	156	194	0.804	0.0000114	2239
Missense in Polyphen		57	78.963	0.72186		958
Synonymous	1.31	68	83.2	0.817	0.00000474	707
Loss of Function	3.39	1	15.3	0.0654	8.26e-7	146

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Essential for mesoderm formation and axial patterning during embryonic development. {ECO:0000250}.
• Disease: DISEASE: Heterotaxy, visceral, 5, autosomal (HTX5) [MIM:270100]: A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. Visceral heterotaxy or situs ambiguus results in randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another. It can been associated with variety of congenital defects including cardiac malformations. HTX5 clinical features include situs inversus viscerum or situs ambiguus, congenital heart defect, transposition of the great vessels ventricular septal defect, atrial septal defect, truncus communis, and dextrocardia. {ECO:0000269|PubMed:19064609, ECO:0000269|PubMed:9354794}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);TGF-Core;Cardiac Progenitor Differentiation;Differentiation Pathway;Endoderm Differentiation;Mesodermal Commitment Pathway;Tgif disruption of Shh signaling;Developmental Biology;Regulation of signaling by NODAL;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;TGF-beta super family signaling pathway canonical;GPCR signaling-G alpha s Epac and ERK;Signaling by NODAL;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;BMP2 signaling TGF-beta MV (Consensus)

Recessive Scores

• pRec: 0.426

Intolerance Scores

• loftool: 0.272
• rvis_EVS: -0.29
• rvis_percentile_EVS: 32.94

Haploinsufficiency Scores

• pHI: 0.657
• hipred: Y
• hipred_score: 0.593
• ghis: 0.514

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.834

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nodal
• 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; liver/biliary system phenotype; respiratory system phenotype; embryo phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; muscle 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); taste/olfaction phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: ndr1
• Affected structure: hatching gland cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;trophectodermal cellular morphogenesis;neural fold formation;liver development;placenta development;embryonic placenta development;maternal placenta development;vasculature development;heart looping;inhibition of neuroepithelial cell differentiation;brain development;embryonic pattern specification;polarity specification of proximal/distal axis;regulation of signaling receptor activity;regulation of gastrulation;positive regulation of vascular endothelial growth factor production;negative regulation of cell development;positive regulation of pathway-restricted SMAD protein phosphorylation;stem cell population maintenance;positive regulation of cell-cell adhesion;BMP signaling pathway;positive regulation of activin receptor signaling pathway;floor plate morphogenesis;endodermal cell differentiation;cell migration involved in gastrulation;regulation of apoptotic process;positive regulation of cysteine-type endopeptidase activity involved in apoptotic process;regulation of MAPK cascade;positive regulation of angiogenesis;positive regulation of transcription by RNA polymerase II;axial mesodermal cell fate specification;mesendoderm development;cell development;digestive tract morphogenesis;embryonic cranial skeleton morphogenesis;formation of anatomical boundary;positive regulation of epithelial cell proliferation;positive regulation of DNA-binding transcription factor activity;embryonic process involved in female pregnancy;maternal process involved in parturition;positive regulation of SMAD protein signal transduction;SMAD protein signal transduction;left lung morphogenesis;negative regulation of androgen receptor signaling pathway;epiblast cell-extraembryonic ectoderm cell signaling involved in anterior/posterior axis specification;positive regulation of ERK1 and ERK2 cascade;transforming growth factor beta receptor signaling pathway involved in primitive streak formation;nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry;positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry;negative regulation of trophoblast cell migration;negative regulation of chorionic trophoblast cell proliferation;regulation of stem cell population maintenance
• Cellular component: extracellular space
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;growth factor activity;morphogen activity;type I activin receptor binding