ITGB4

integrin subunit beta 4, the group of CD molecules|Integrin beta subunits|Fibronectin type III domain containing

Basic information

Region (hg38): 17:75721328-75757818

Links

ENSG00000132470 ∙ NCBI:3691 ∙ OMIM:147557 ∙ HGNC:6158 ∙ Uniprot:P16144 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• junctional epidermolysis bullosa, non-Herlitz type (Strong), mode of inheritance: AR
• junctional epidermolysis bullosa with pyloric atresia (Strong), mode of inheritance: AR
• junctional epidermolysis bullosa with pyloric atresia (Definitive), mode of inheritance: AR
• aplasia cutis congenita (Supportive), mode of inheritance: AD
• generalized junctional epidermolysis bullosa non-Herlitz type (Supportive), mode of inheritance: AR
• junctional epidermolysis bullosa with pyloric atresia (Supportive), mode of inheritance: AR
• epidermolysis bullosa simplex 5C, with pyloric atresia (Supportive), mode of inheritance: AR
• localized junctional epidermolysis bullosa, non-Herlitz type (Supportive), mode of inheritance: AR
• junctional epidermolysis bullosa, non-Herlitz type (Strong), mode of inheritance: AR
• epidermolysis bullosa simplex 1C, localized (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epidermolysis bullosa, junctional 5A, intermediate; Epidermolysis bullosa, junctional 5B, with pyloric atresia	AR	Renal	In addition to gastrointestinal anomalies, the condition may include ureterovesical obstruction, and prompt recognition and treatment may be beneficial in terms of renal function	Dermatologic; Gastrointestinal; Renal	6177243; 7545057; 9674902; 9792864; 10484780; 10792571; 12485428; 18348258; 20301336; 20955205; 21969027; 22354727; 22674212

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ITGB4 gene.

• not provided (76 variants)
• Junctional epidermolysis bullosa with pyloric atresia (18 variants)
• Epidermolysis bullosa simplex 1C, localized (1 variants)
• Epidermolysis bullosa, junctional 5A, intermediate;Junctional epidermolysis bullosa with pyloric atresia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITGB4 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	484	18	506
missense	9	2	239	50	9	309
nonsense	21	2	2			25
start loss						0
frameshift	49	5	1			55
inframe indel	1		2		1	4
splice donor/acceptor (+/-2bp)	3	22	1			26
splice region	2		12	86	6	106
non coding	1		7	288	71	367
Total	84	31	256	822	99

Highest pathogenic variant AF is 0.0000197

Variants in ITGB4

This is a list of pathogenic ClinVar variants found in the ITGB4 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-75721464-A-C		Junctional epidermolysis bullosa with pyloric atresia	Uncertain significance (Jan 12, 2018)
17-75721498-G-C		Junctional epidermolysis bullosa with pyloric atresia	Conflicting classifications of pathogenicity (Apr 01, 2023)
17-75721555-C-T		Junctional epidermolysis bullosa with pyloric atresia	Uncertain significance (Jan 13, 2018)
17-75721600-T-C		Junctional epidermolysis bullosa with pyloric atresia	Uncertain significance (Jun 14, 2016)
17-75724713-C-T			Uncertain significance (Jun 30, 2022)
17-75724717-G-A			Uncertain significance (Aug 09, 2022)
17-75724718-C-T			Likely benign (Jul 11, 2023)
17-75724729-G-A			Pathogenic (Nov 08, 2023)
17-75724737-C-T			Likely benign (Jun 18, 2018)
17-75724746-G-A			Likely benign (Jan 18, 2024)
17-75724752-T-C			Likely benign (Dec 22, 2022)
17-75724760-C-T		ITGB4-related disorder	Benign (Dec 30, 2023)
17-75724763-C-T			Likely benign (Oct 06, 2023)
17-75724772-T-C			Likely benign (Nov 02, 2023)
17-75724778-C-G			Likely benign (Dec 03, 2023)
17-75724783-G-A			Likely pathogenic (Jan 23, 2023)
17-75724788-T-C			Uncertain significance (Jul 03, 2023)
17-75724792-C-T			Likely benign (Jan 24, 2024)
17-75724793-G-A			Likely benign (Jan 01, 2023)
17-75724799-C-T			Likely benign (Jan 31, 2023)
17-75724820-A-G			Benign (Mar 03, 2015)
17-75726990-G-A			Likely benign (Mar 09, 2019)
17-75727159-G-A			Benign (Mar 03, 2015)
17-75727175-G-A			Likely benign (Feb 25, 2023)
17-75727178-C-T			Likely benign (Apr 25, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ITGB4	protein_coding	protein_coding	ENST00000200181	39	36492

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.53e-19	1.00	125600	0	148	125748	0.000589

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.374	1086	1.12e+3	0.969	0.0000822	11805
Missense in Polyphen		454	500.59	0.90694		5219
Synonymous	-0.759	507	486	1.04	0.0000375	3693
Loss of Function	4.32	45	89.0	0.505	0.00000462	986

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000813	0.000811
Ashkenazi Jewish	0.000998	0.000993
East Asian	0.00126	0.00125
Finnish	0.00	0.00
European (Non-Finnish)	0.000690	0.000677
Middle Eastern	0.00126	0.00125
South Asian	0.000605	0.000588
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Integrin alpha-6/beta-4 is a receptor for laminin. Plays a critical structural role in the hemidesmosome of epithelial cells. Is required for the regulation of keratinocyte polarity and motility. ITGA6:ITGB4 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGA6:ITGB4 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:22351760). ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464). {ECO:0000269|PubMed:12482924, ECO:0000269|PubMed:19403692, ECO:0000269|PubMed:20682778, ECO:0000269|PubMed:22351760, ECO:0000269|PubMed:28873464}.
• Disease: DISEASE: Epidermolysis bullosa letalis, with pyloric atresia (EB- PA) [MIM:226730]: An autosomal recessive, frequently lethal, epidermolysis bullosa with variable involvement of skin, nails, mucosa, and with variable effects on the digestive system. It is characterized by mucocutaneous fragility, aplasia cutis congenita, and gastrointestinal atresia, which most commonly affects the pylorus. Pyloric atresia is a primary manifestation rather than a scarring process secondary to epidermolysis bullosa. {ECO:0000269|PubMed:10873890, ECO:0000269|PubMed:11251584, ECO:0000269|PubMed:11328943, ECO:0000269|PubMed:9422533, ECO:0000269|PubMed:9546354, ECO:0000269|PubMed:9792864, ECO:0000269|PubMed:9892956}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Generalized atrophic benign epidermolysis bullosa (GABEB) [MIM:226650]: A non-lethal, adult form of junctional epidermolysis bullosa characterized by life-long blistering of the skin, associated with hair and tooth abnormalities. {ECO:0000269|PubMed:10792571}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epidermolysis bullosa simplex, Weber-Cockayne type (WC- EBS) [MIM:131800]: A form of intraepidermal epidermolysis bullosa characterized by blistering limited to palmar and plantar areas of the skin. {ECO:0000269|PubMed:12485428}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);ECM-receptor interaction - Homo sapiens (human);Focal adhesion - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);miR-targeted genes in epithelium - TarBase;miR-targeted genes in muscle cell - TarBase;Integrin-mediated Cell Adhesion;Arrhythmogenic Right Ventricular Cardiomyopathy;Alpha 6 Beta 4 signaling pathway;Primary Focal Segmental Glomerulosclerosis FSGS;Focal Adhesion;TGF-beta Signaling Pathway;Regulation of Apoptosis by Parathyroid Hormone-related Protein;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Assembly of collagen fibrils and other multimeric structures;Alpha6Beta4Integrin;Laminin interactions;Collagen formation;Extracellular matrix organization;Integrin;EGFR1;Validated transcriptional targets of TAp63 isoforms;a6b1 and a6b4 Integrin signaling;Syndecan interactions;Non-integrin membrane-ECM interactions;Type I hemidesmosome assembly;Cell junction organization;Cell-Cell communication;Validated targets of C-MYC transcriptional repression;Alpha6 beta4 integrin-ligand interactions;Validated transcriptional targets of AP1 family members Fra1 and Fra2 (Consensus)

Intolerance Scores

• loftool: 0.0863
• rvis_EVS: -3.01
• rvis_percentile_EVS: 0.53

Haploinsufficiency Scores

• pHI: 0.170
• hipred: Y
• hipred_score: 0.706
• ghis: 0.612

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.779

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Itgb4
• 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); growth/size/body region phenotype; taste/olfaction phenotype; craniofacial phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory 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); 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); 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); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; vision/eye phenotype

Gene ontology

• Biological process: autophagy;cell adhesion;cell-matrix adhesion;integrin-mediated signaling pathway;response to wounding;cell migration;extracellular matrix organization;hemidesmosome assembly;cell adhesion mediated by integrin;nail development;skin development;mesodermal cell differentiation;digestive tract development;cell motility;renal system development;amelogenesis
• Cellular component: plasma membrane;focal adhesion;integrin complex;cell surface;cell junction;hemidesmosome;cell leading edge;receptor complex;extracellular exosome
• Molecular function: G protein-coupled receptor binding;integrin binding;protein binding;insulin-like growth factor I binding;neuregulin binding