ITGA8

protein-coding

integrin subunit alpha 8, the group of Integrin alpha subunits

Gene summary

Integrins are heterodimeric transmembrane receptor proteins that mediate numerous cellular processes including cell adhesion, cytoskeletal rearrangement, and activation of cell signaling pathways. Integrins are composed of alpha and beta subunits. This gene encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1 protein. The encoded protein is a single-pass type 1 membrane protein that contains multiple FG-GAP repeats. This repeat is predicted to fold into a beta propeller structure. This gene regulates the recruitment of mesenchymal cells into epithelial structures, mediates cell-cell interactions, and regulates neurite outgrowth of sensory and motor neurons. The integrin alpha8beta1 protein thus plays an important role in wound-healing and organogenesis. Mutations in this gene have been associated with renal hypodysplasia/aplasia-1 (RHDA1) and with several animal models of chronic kidney disease. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2014]

MANE transcript

NM_003638.3

Inheritance

ClinVar variants

P:24U:218B:103

Top phenotype

Renal hypodysplasia/aplasia 1

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr10:15,513,954-15,719,922

External References & Databases

Ensembl (ENSG00000077943)

Transcript & Mutation Effects

hg38 • Region Span ~206.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

bilateral renal agenesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015986

Submitter: Orphanet

renal hypodysplasia/aplasia 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0024519

Submitter: Ambry Genetics

renal hypodysplasia/aplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024519

Submitter: PanelApp Australia

renal hypodysplasia/aplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024519

Submitter: G2P

renal hypodysplasia/aplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024519

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Renal hypodysplasia/aplasia 1AR

Manifestation: Renal

Intervention: General

Rationale: 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

Refs: 24439109

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITGA8 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 216

Inborn genetic diseasesTotal: 168

ITGA8-related disorderTotal: 31

Renal hypodysplasia/aplasia 1Total: 25

not specifiedTotal: 13

Fetal anomalies with a likely genetic causeTotal: 1

ITGA8-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003638.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	76 clinvar	12 clinvar	89
missense	1 clinvar	1 clinvar	213 clinvar	12 clinvar	3 clinvar	230
nonsense	6 clinvar	3 clinvar	2 clinvar			11
start loss						0
frameshift	5 clinvar	2 clinvar				7
splice donor/acceptor (+/-2bp)		6 clinvar	2 clinvar			8
Total	12	12	218	88	15	345

Highest pathogenic variant AF is 0.000011159068

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003638.3	RefSeq	NP_003629.2	30	MANE Select
ENST00000378076.4	Ensembl	ENSP00000367316.3	30	MANE Select
NM_001291494.2	RefSeq	NP_001278423.1	29	Standard
ENST00000882526.1	Ensembl	ENSP00000552585.1	29	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
itga8	Danio rerio	Structure: neuromast hair cell Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

itga8

Danio rerio

Structure: neuromast hair cell

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Cell adhesion molecules (CAMs) - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Dilated cardiomyopathy (DCM) - Homo sapiens (human)

Biological Process

metanephros development
kidney development
cell-matrix adhesion
integrin-mediated signaling pathway
brain development

Molecular Function

metal ion binding

Cellular Component

endoplasmic reticulum
plasma membrane
focal adhesion
integrin complex
cell surface

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378076
Coding exons: 30
Length: 206177
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125748
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.272	593	575	1.03	0.0000296	6939
Missense (PolyPhen)		230	232.16	0.99072		2779
Synonymous	-0.996	234	215	1.09	0.0000124	2012
Loss of Function	3.74	31	63.0	0.492	0.00000329	742

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00065	0.00065	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00056	0.00056	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures. It recognizes the sequence R-G-D in a wide array of ligands including TNC, FN1, SPP1 TGFB1, TGFB3 and VTN. NPNT is probably its functional ligand in kidney genesis. Neuronal receptor for TNC it mediates cell-cell interactions and regulates neurite outgrowth of sensory and motor neurons. {ECO:0000269|PubMed:12415008, ECO:0000269|PubMed:15721307}.;

Recessive Scores

pRec: 0.190

Intolerance Scores

RVIS EVS: -0.79
RVIS percentile EVS: 12.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.877

Gene Damage Prediction

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