NRG1

neuregulin 1, the group of I-set domain containing|Neuregulins

Basic information

Region (hg38): 8:31639221-32855666

Previous symbols: [ "HGL", "NRG1-IT2" ]

Links

ENSG00000157168 ∙ NCBI:3084 ∙ OMIM:142445 ∙ HGNC:7997 ∙ Uniprot:Q02297 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• schizophrenia 6 (Limited), mode of inheritance: AR

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NRG1 gene.

• not provided (36 variants)
• not specified (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NRG1 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				8	3	11
missense			1	2	3	6
nonsense			1			1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	2	10	6

Variants in NRG1

This is a list of pathogenic ClinVar variants found in the NRG1 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-31639995-G-A		NRG1-related disorder	Benign (Oct 28, 2019)
8-31639995-G-C			not provided (-)
8-31639999-C-G		NRG1-related disorder	Likely benign (Feb 21, 2019)
8-31640010-G-A		NRG1-related disorder	Benign (Nov 25, 2019)
8-31640027-C-T			not provided (-)
8-31640092-G-A			not provided (-)
8-31640107-C-A			not provided (-)
8-31640156-G-A			Benign (Dec 15, 2021)
8-31640175-C-T			not provided (-)
8-31640208-T-C		NRG1-related disorder	Benign (Aug 07, 2019)
8-31640283-AGGC-A		NRG1-related disorder	Likely benign (Jul 17, 2020)
8-31640296-G-A			Likely benign (Sep 01, 2022)
8-31640334-C-T			not provided (-)
8-31640344-G-T			not provided (-)
8-31640457-C-T		NRG1-related disorder	Benign (Mar 12, 2019)
8-32548756-A-C			not provided (-)
8-32595838-C-G		NRG1-related disorder	Likely benign (Sep 17, 2019)
8-32595840-G-A		NRG1-related disorder	Benign (Mar 27, 2019)
8-32595867-C-T			not provided (-)
8-32595868-G-A			Benign (Aug 24, 2018)
8-32595889-C-T			Likely benign (Jun 10, 2018)
8-32595960-A-T		not specified	Uncertain significance (Aug 02, 2021)
8-32605565-G-A			Likely benign (Apr 12, 2018)
8-32605615-T-C		Hereditary spastic paraplegia	Affects (-)
8-32614527-T-C		NRG1-related disorder	Benign (Dec 31, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NRG1	protein_coding	protein_coding	ENST00000356819	13	1125647

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.997	0.00335	125699	0	7	125706	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.637	343	378	0.908	0.0000214	4234
Missense in Polyphen		113	140.95	0.80168		1490
Synonymous	0.954	129	144	0.899	0.00000868	1245
Loss of Function	4.57	3	30.0	0.100	0.00000154	367

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000912	0.0000905
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000545	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000354	0.0000352
Middle Eastern	0.0000545	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Isoform 10 may play a role in motor and sensory neuron development. Binds to ERBB4 (PubMed:10867024, PubMed:7902537). Binds to ERBB3 (PubMed:20682778). Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling. Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:20682778). Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (By similarity). {ECO:0000250|UniProtKB:P43322, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:1348215, ECO:0000269|PubMed:20682778, ECO:0000269|PubMed:7902537}.
• Disease: DISEASE: Note=A chromosomal aberration involving NRG1 produces gamma-heregulin. Translocation t(8;11) with TENM4. The translocation fuses the 5'-end of TENM4 to NRG1 (isoform 8). The product of this translocation was first thought to be an alternatively spliced isoform. Gamma-heregulin is a soluble activating ligand for the ERBB2-ERBB3 receptor complex and acts as an autocrine growth factor in a specific breast cancer cell line (MDA-MB-175). Not detected in breast carcinoma samples, including ductal, lobular, medullary, and mucinous histological types, neither in other breast cancer cell lines.
• Pathway: ErbB signaling pathway - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;EGF-Core;MicroRNAs in cardiomyocyte hypertrophy;Cardiac Progenitor Differentiation;Cardiac Hypertrophic Response;Apoptosis-related network due to altered Notch3 in ovarian cancer;Nuclear Receptors Meta-Pathway;NRF2 pathway;ErbB Signaling Pathway;SHC1 events in ERBB2 signaling;Signaling by PTK6;Disease;Signal Transduction;neuroregulin receptor degredation protein-1 controls erbb3 receptor recycling;ERBB2 Activates PTK6 Signaling;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;ErbB4 signaling events;GPCR signaling-G alpha s Epac and ERK;Downregulation of ERBB2:ERBB3 signaling;Downregulation of ERBB2 signaling;GPCR signaling-G alpha s PKA and ERK;agrin in postsynaptic differentiation;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;PIP3 activates AKT signaling;GRB2 events in ERBB2 signaling;Signaling by Non-Receptor Tyrosine Kinases;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K events in ERBB2 signaling;GRB7 events in ERBB2 signaling;Signaling by ERBB2;ERBB2 Regulates Cell Motility;SHC1 events in ERBB4 signaling;PI3K/AKT Signaling in Cancer;PI3K events in ERBB4 signaling;GPCR signaling-G alpha i;Nuclear signaling by ERBB4;Signaling by ERBB4;Signaling by Receptor Tyrosine Kinases;ErbB2/ErbB3 signaling events;Intracellular signaling by second messengers;Diseases of signal transduction;Glypican 1 network;Validated transcriptional targets of deltaNp63 isoforms;ErbB receptor signaling network (Consensus)

Recessive Scores

• pRec: 0.608

Intolerance Scores

• loftool: 0.325
• rvis_EVS: 1.07
• rvis_percentile_EVS: 91.71

Haploinsufficiency Scores

• pHI: 0.879
• hipred: Y
• hipred_score: 0.654
• ghis: 0.386

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.965

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Nrg1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region 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); endocrine/exocrine gland phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); vision/eye 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); reproductive system 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); embryo phenotype

Zebrafish Information Network

• Gene name: nrg1
• Affected structure: interneuromast cell
• Phenotype tag: abnormal
• Phenotype quality: increased process quality

Gene ontology

• Biological process: MAPK cascade;activation of MAPK activity;cell morphogenesis;cardiac conduction system development;ventricular trabecula myocardium morphogenesis;cell communication;activation of transmembrane receptor protein tyrosine kinase activity;nervous system development;synapse assembly;locomotory behavior;positive regulation of cell population proliferation;regulation of signaling receptor activity;positive regulation of gene expression;neural crest cell development;peptidyl-tyrosine phosphorylation;glial cell fate commitment;chemorepulsion involved in interneuron migration from the subpallium to the cortex;myelination in peripheral nervous system;mammary gland development;activation of protein kinase B activity;intracellular signal transduction;ERBB signaling pathway;ERBB2 signaling pathway;ERBB3 signaling pathway;wound healing;negative regulation of protein catabolic process;regulation of protein homodimerization activity;regulation of protein heterodimerization activity;neurotransmitter receptor metabolic process;negative regulation of transcription, DNA-templated;positive regulation of Ras protein signal transduction;phosphatidylinositol phosphorylation;neuron fate commitment;oligodendrocyte differentiation;negative regulation of secretion;positive regulation of striated muscle cell differentiation;positive regulation of protein kinase B signaling;cardiac muscle cell differentiation;cardiac muscle cell myoblast differentiation;endocardial cell differentiation;positive regulation of protein tyrosine kinase activity;positive regulation of calcineurin-NFAT signaling cascade;postsynapse to nucleus signaling pathway;regulation of cell motility;positive regulation of cardiac muscle cell differentiation;negative regulation of neuron migration
• Cellular component: extracellular region;extracellular space;nucleoplasm;cytoplasm;integral component of plasma membrane;membrane;axon;neuromuscular junction;glutamatergic synapse;GABA-ergic synapse
• Molecular function: transcription coregulator activity;protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;signaling receptor binding;cytokine activity;ErbB-2 class receptor binding;integrin binding;growth factor activity;protein tyrosine kinase activator activity;transmembrane receptor protein tyrosine kinase activator activity;receptor tyrosine kinase binding;ErbB-3 class receptor binding;chemorepellent activity;phosphatidylinositol-4,5-bisphosphate 3-kinase activity