GeneBe

ITGB4

protein-coding

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

Gene summary

Integrins are heterodimers comprised of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000213.5

Inheritance

AR, SD, AD

ClinVar variants

P:164U:558B:682

Top phenotype

Epidermolysis bullosa, junctional 5A, intermediate; Epidermolysis bullosa, junctional 5B, with pyloric atresia

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr17:75,721,328-75,757,818

External References & Databases

Ensembl (ENSG00000132470)NCBI Gene (3691)OMIM (147557)HGNC:6158GenCCUniProt (P16144)AlphaFoldClinVar (ITGB4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~36.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

junctional epidermolysis bullosa, non-Herlitz typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009180

Submitter: Genomics England PanelApp

junctional epidermolysis bullosa with pyloric atresiaSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0009183

Submitter: PanelApp Australia

generalized junctional epidermolysis bullosa non-Herlitz typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019307

Submitter: Orphanet

junctional epidermolysis bullosa, non-Herlitz typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009180

Submitter: Labcorp Genetics (formerly Invitae)

epidermolysis bullosa simplex 1C, localizedLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007551

Submitter: Labcorp Genetics (formerly Invitae)

junctional epidermolysis bullosa with pyloric atresiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009183

Submitter: G2P

epidermolysis bullosa simplexDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017610

Submitter: G2P

junctional epidermolysis bullosaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017612

Submitter: Natera

junctional epidermolysis bullosa with pyloric atresiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009183

Submitter: Ambry Genetics

junctional epidermolysis bullosa with pyloric atresiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009183

Submitter: Genomics England PanelApp

junctional epidermolysis bullosa with pyloric atresiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009183

Submitter: Orphanet

epidermolysis bullosa, junctional 5A, intermediateSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0030768

Submitter: PanelApp Australia

localized junctional epidermolysis bullosa, non-Herlitz typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016673

Submitter: Orphanet

epidermolysis bullosa simplex 5C, with pyloric atresiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012807

Submitter: Orphanet

aplasia cutis congenitaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007145

Submitter: Orphanet

Clinical Genomic Database (CGD)

Epidermolysis bullosa, junctional 5A, intermediate; Epidermolysis bullosa, junctional 5B, with pyloric atresiaAR

Manifestation: Dermatologic; Gastrointestinal; Renal

Intervention: Renal

Rationale: In addition to gastrointestinal anomalies, the condition may include ureterovesical obstruction, and prompt recognition and treatment may be beneficial in terms of renal function

Refs: 6177243; 7545057; 9674902; 9792864; 10484780; 10792571; 12485428; 18348258; 20301336; 20955205; 21969027; 22354727; 22674212Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITGB4 variants in ClinVar

18 Conditions Cataloged
not providedTotal: 1380
Junctional epidermolysis bullosa with pyloric atresiaTotal: 546
Epidermolysis bullosa, junctional 5A, intermediateTotal: 393
Inborn genetic diseasesTotal: 309
ITGB4-related disorderTotal: 141
not specifiedTotal: 69
Epidermolysis bullosa simplex 1C, localizedTotal: 5
Deficiency of galactokinaseTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000213.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
17
clinvar
568
clinvar
12
clinvar
 598
missense
10
clinvar
9
clinvar
532
clinvar
100
clinvar
2
clinvar
 653
nonsense
26
clinvar
11
clinvar
1
clinvar
 38
start loss
0
frameshift
52
clinvar
20
clinvar
3
clinvar
 75
splice donor/acceptor (+/-2bp)
5
clinvar
30
clinvar
5
clinvar
 40
Total9371558668141404

Highest pathogenic variant AF is 0.000057662688

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000213.5RefSeqNP_000204.339MANE Select
ENST00000200181.8EnsemblENSP00000200181.339MANE Select
NM_001005619.2RefSeqNP_001005619.139Standard
NM_001005731.3RefSeqNP_001005731.138Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • autophagy
  • cell adhesion
  • cell-matrix adhesion
  • integrin-mediated signaling pathway
  • response to wounding

Molecular Function

  • G protein-coupled receptor binding
  • integrin binding
  • protein binding
  • insulin-like growth factor I binding
  • neuregulin binding

Cellular Component

  • plasma membrane
  • focal adhesion
  • integrin complex
  • cell surface
  • cell junction

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000200181
Coding exons
39
Length
36492
Individuals with no LoFs
125600
Homozygous LoFs
0
Heterozygous LoFs
148
Defined
125748
p
0.000589
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.37410861.12e+30.9690.000082211805
Missense (PolyPhen)454500.590.906945219
Synonymous-0.7595074861.040.00003753693
Loss of Function4.324589.00.5050.00000462986

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000430.00043rare
Latino/Admixed American0.000380.00038rare
Ashkenazi Jewish0.00100.00099rare
East Asian0.00130.0013notable
Finnish00.0absent
European (Non-Finnish)0.000690.00068rare
South Asian0.000610.00059rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Intolerance Scores

LoFtool
0.0863
RVIS EVS
-3.01
RVIS percentile EVS
0.53

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.779

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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