ERBB4

erb-b2 receptor tyrosine kinase 4, the group of Erb-b2 receptor tyrosine kinases|MicroRNA protein coding host genes

Basic information

Region (hg38): 2:211375716-212538841

Links

ENSG00000178568 ∙ NCBI:2066 ∙ OMIM:600543 ∙ HGNC:3432 ∙ Uniprot:Q15303 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis type 19 (Moderate), mode of inheritance: AD
• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• amyotrophic lateral sclerosis type 19 (Limited), mode of inheritance: AD
• amyotrophic lateral sclerosis type 19 (Strong), mode of inheritance: AD
• amyotrophic lateral sclerosis type 19 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 19	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	24119685

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERBB4 gene.

• not provided (357 variants)
• Inborn genetic diseases (24 variants)
• Amyotrophic lateral sclerosis type 19 (20 variants)
• ERBB4-related condition (14 variants)
• not specified (8 variants)
• Amyotrophic lateral sclerosis (8 variants)
• Amyotrophic lateral sclerosis type 10 (2 variants)
• ERBB4-related Non-syndromic intellectual disability or epilepsy (1 variants)
• ERBB4-associated epilepsy syndrome (1 variants)
• Frontotemporal dementia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERBB4 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				73	9	82
missense	1	2	138	8		149
nonsense			1			1
start loss						0
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)			2			2
splice region			9	13	8	30
non coding				34	99	133
Total	3	3	141	115	108

Highest pathogenic variant AF is 0.00000657

Variants in ERBB4

This is a list of pathogenic ClinVar variants found in the ERBB4 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-211380227-G-A			Benign (Feb 24, 2021)
2-211383616-T-C			Uncertain significance (Oct 21, 2022)
2-211383633-G-A			Likely benign (Jul 25, 2022)
2-211383651-C-T		ERBB4-related disorder	Likely benign (Mar 23, 2023)
2-211383652-G-A			Uncertain significance (Jan 14, 2023)
2-211383654-C-A			Likely benign (Nov 30, 2021)
2-211383664-C-T		Amyotrophic lateral sclerosis type 19	Uncertain significance (Sep 23, 2022)
2-211383681-C-A			Uncertain significance (Jun 04, 2023)
2-211383683-C-T			Uncertain significance (Aug 13, 2021)
2-211383695-C-A		Lung cancer	Pathogenic (Jun 15, 2021)
2-211383704-C-G			Uncertain significance (Dec 16, 2022)
2-211383718-C-T			Uncertain significance (Sep 02, 2021)
2-211383719-G-A		Amyotrophic lateral sclerosis type 19	Conflicting classifications of pathogenicity (Apr 01, 2024)
2-211383721-A-C			Uncertain significance (Sep 11, 2023)
2-211383723-C-T			Likely benign (Jan 17, 2022)
2-211383728-C-T		Amyotrophic lateral sclerosis	Likely pathogenic (Jul 31, 2020)
2-211383763-T-C		Inborn genetic diseases	Uncertain significance (Feb 14, 2023)
2-211383768-G-A			Likely benign (Jan 08, 2024)
2-211383777-G-A			Likely benign (Jul 31, 2023)
2-211383796-G-A			Likely benign (Dec 04, 2023)
2-211383807-G-A			Likely benign (Jan 09, 2024)
2-211383810-G-A			Likely benign (May 03, 2022)
2-211383816-G-A			Likely benign (May 05, 2023)
2-211383834-C-T			Likely benign (Dec 19, 2022)
2-211383835-G-A			Uncertain significance (Nov 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERBB4	protein_coding	protein_coding	ENST00000342788	28	1163120

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000884	125729	0	19	125748	0.0000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.01	576	729	0.790	0.0000394	8616
Missense in Polyphen		119	218.55	0.54451		2633
Synonymous	-2.23	300	255	1.18	0.0000134	2472
Loss of Function	6.63	12	73.3	0.164	0.00000404	850

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000214	0.000214
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000218	0.000217
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.000218	0.000217
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750, ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115, ECO:0000269|PubMed:9334263}.
• Disease: DISEASE: Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:24119685}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;EGF-Core;JAK-STAT-Core;EV release from cardiac cells and their functional effects;Association Between Physico-Chemical Features and Toxicity Associated Pathways;ErbB Signaling Pathway;SHC1 events in ERBB2 signaling;Signaling by PTK6;Disease;Signal Transduction;g-secretase mediated erbb4 signaling pathway;role of erbb2 in signal transduction and oncology;Prolactin;ERBB2 Activates PTK6 Signaling;Downregulation of ERBB4 signaling;ErbB4 signaling events;Downregulation of ERBB2 signaling;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;Signaling by Nuclear Receptors;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;Signaling by ERBB2;Estrogen-dependent gene expression;ERBB2 Regulates Cell Motility;SHC1 events in ERBB4 signaling;PI3K/AKT Signaling in Cancer;PI3K events in ERBB4 signaling;Nuclear signaling by ERBB4;Signaling by ERBB4;Signaling by Receptor Tyrosine Kinases;ESR-mediated signaling;Intracellular signaling by second messengers;Diseases of signal transduction;ErbB receptor signaling network (Consensus)

Recessive Scores

• pRec: 0.402

Intolerance Scores

• loftool: 0.147
• rvis_EVS: -1.97
• rvis_percentile_EVS: 1.79

Haploinsufficiency Scores

• pHI: 0.995
• hipred: Y
• hipred_score: 0.793
• ghis: 0.612

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Erbb4
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo 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); normal phenotype; reproductive 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); hematopoietic system 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); cellular phenotype; immune system phenotype; endocrine/exocrine gland 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); muscle phenotype

Zebrafish Information Network

• Gene name: erbb4a
• Affected structure: optic tectum
• Phenotype tag: abnormal
• Phenotype quality: decreased process quality

Gene ontology

• Biological process: MAPK cascade;neural crest cell migration;positive regulation of protein phosphorylation;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;nervous system development;synapse assembly;heart development;lactation;cell population proliferation;positive regulation of cell population proliferation;negative regulation of cell population proliferation;embryonic pattern specification;positive regulation of phosphatidylinositol 3-kinase signaling;cell migration;peptidyl-tyrosine phosphorylation;central nervous system morphogenesis;olfactory bulb interneuron differentiation;regulation of cell migration;ERBB2 signaling pathway;positive regulation of tyrosine phosphorylation of STAT protein;mitochondrial fragmentation involved in apoptotic process;cell fate commitment;positive regulation of transcription, DNA-templated;positive regulation of JAK-STAT cascade;protein autophosphorylation;phosphatidylinositol phosphorylation;positive regulation of protein kinase B signaling;positive regulation of cardiac muscle cell proliferation;mammary gland epithelial cell differentiation;mammary gland alveolus development;cardiac muscle tissue regeneration;positive regulation of ERK1 and ERK2 cascade;cellular response to epidermal growth factor stimulus;positive regulation of protein localization to cell surface;regulation of cell motility;negative regulation of neuron migration
• Cellular component: extracellular region;nucleus;nucleoplasm;mitochondrion;mitochondrial matrix;cytosol;plasma membrane;integral component of plasma membrane;basal plasma membrane;basolateral plasma membrane;receptor complex;postsynaptic membrane;glutamatergic synapse;GABA-ergic synapse;integral component of presynaptic membrane;integral component of postsynaptic density membrane
• Molecular function: protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;epidermal growth factor receptor binding;protein binding;ATP binding;protein homodimerization activity;transcription regulatory region DNA binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity