GeneBe

COL4A5

protein-coding

collagen type IV alpha 5 chain, the group of Collagens

Gene summary

This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

Previous symbols:
  • ASLN
  • ATS

MANE transcript

NM_033380.3

Inheritance

XL

ClinVar variants

P:1547U:762B:653

Top phenotype

Alport syndrome 1, X-linked

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:108,439,838-108,697,545

External References & Databases

Ensembl (ENSG00000188153)NCBI Gene (1287)OMIM (303630)HGNC:2207GenCCUniProt (P29400)AlphaFoldClinVar (COL4A5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~257.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked Alport syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010520

Submitter: Genomics England PanelApp

X-linked Alport syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010520

Submitter: Labcorp Genetics (formerly Invitae)

Alport syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018965

Submitter: ClinGen

COL4A5 was first reported in relation to X-linked Alport syndrome in 1990 (Myers et al., 2339699). Eight missense, frameshift, nonsense and splice-site variants reported in humans were included in this curation, however approximately 1000 pathogenic or likely pathogenic variants in this gene have been reported in ClinVar. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least 8 probands in 7 publications (10563487, 14993485, 23085274, 25572247, 27725546, 28542346, 27796712). Variants in this gene segregated with disease in 18 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by knock-in mouse models and expression studies in humans (15153557, 30582011, 16301374). In summary, COL4A5 is definitely associated with X-linked Alport syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 3/19/19 (SOP Version 6).

X-linked Alport syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010520

Submitter: Myriad Women's Health

Alport syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0018965

Submitter: G2P

X-linked Alport syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010520

Submitter: Natera

X-linked Alport syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010520

Submitter: Orphanet

Clinical Genomic Database (CGD)

Alport syndrome 1, X-linkedXL

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic; Renal

Intervention: Ophthalmologic; Renal

Rationale: In Alport syndrome, medical treatment related to renal sequelae (eg, with ACE inhibitors, ARBs) may be beneficial related to delaying renal failure, as well as with overall life expectancy, though dialysis/renal transplantation may be required; Corneal protection may be beneficial in individuals with recurrent corneal erosions

Comments: Treatment of renal issues (eg, with antihypertensive agents, ACE inhibitors, etc.) can be helpful, but does not appear to affect natural history

Refs: 20773074; 14856448; 626446; 7033680; 3728466; 2349482; 1483700; 1635357; 1598909; 7706490; 8825605; 8651292; 8940267; 8651296; 9195222; 20881942; 21505094; 21848006; 21897443; 21332469; 22166944; 20301386; 22166847; 22237748; 22335431; 22811928; 22921432; 22919268; 22997344Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL4A5 variants in ClinVar

36 Conditions Cataloged
not providedTotal: 2164
X-linked Alport syndromeTotal: 1375
not specifiedTotal: 192
COL4A5-related disordersTotal: 181
COL4A5-related disorderTotal: 160
Inborn genetic diseasesTotal: 153
Alport syndromeTotal: 54
HematuriaTotal: 40

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033380.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
2
clinvar
81
clinvar
459
clinvar
18
clinvar
 561
missense
191
clinvar
636
clinvar
616
clinvar
161
clinvar
15
clinvar
 1619
nonsense
82
clinvar
78
clinvar
15
clinvar
 175
start loss
3
clinvar
1
clinvar
 4
frameshift
192
clinvar
144
clinvar
 336
splice donor/acceptor (+/-2bp)
102
clinvar
115
clinvar
50
clinvar
 267
Total571976762620332962

Highest pathogenic variant AF is 0.000046288147

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_033380.3RefSeqNP_203699.153MANE Select
ENST00000328300.11EnsemblENSP00000331902.753MANE Select
NM_000495.5RefSeqNP_000486.151Standard
ENST00000361603.7EnsemblENSP00000354505.251Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
col4a5Danio rerio

Structure: retinal ganglion 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)
  • ECM-receptor interaction - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • Relaxin signaling pathway - Homo sapiens (human)
  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

  • neuromuscular junction development
  • extracellular matrix organization
  • collagen-activated tyrosine kinase receptor signaling pathway

Molecular Function

  • extracellular matrix structural constituent
  • extracellular matrix structural constituent conferring tensile strength

Cellular Component

  • extracellular region
  • collagen type IV trimer
  • extracellular space
  • endoplasmic reticulum lumen
  • extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000328300
Coding exons
53
Length
257702
Individuals with no LoFs
125728
Homozygous LoFs
1
Heterozygous LoFs
6
Defined
125735
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.504746540.7250.000046710558
Missense (PolyPhen)66107.110.616181643
Synonymous-0.3562222151.030.00001593773
Loss of Function6.59661.90.09690.000004151163

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000230.00018rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000630.000046rare
European (Non-Finnish)0.0000380.000026rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.;
Disease
DISEASE: Alport syndrome, X-linked (APSX) [MIM:301050]: A syndrome that is characterized by progressive glomerulonephritis, renal failure, sensorineural deafness, specific eye abnormalities (lenticonous and macular flecks), and glomerular basement membrane defects. The disorder shows considerable heterogeneity in that families differ in the age of end-stage renal disease and the occurrence of deafness. {ECO:0000269|PubMed:10094548, ECO:0000269|PubMed:10561141, ECO:0000269|PubMed:10563487, ECO:0000269|PubMed:10684360, ECO:0000269|PubMed:10862091, ECO:0000269|PubMed:11004279, ECO:0000269|PubMed:11223851, ECO:0000269|PubMed:1352287, ECO:0000269|PubMed:1363780, ECO:0000269|PubMed:1376965, ECO:0000269|PubMed:1672282, ECO:0000269|PubMed:24522658, ECO:0000269|PubMed:7599631, ECO:0000269|PubMed:7853788, ECO:0000269|PubMed:8406498, ECO:0000269|PubMed:8651292, ECO:0000269|PubMed:8651296, ECO:0000269|PubMed:8829632, ECO:0000269|PubMed:8940267, ECO:0000269|PubMed:9150741, ECO:0000269|PubMed:9452056, ECO:0000269|PubMed:9848783}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Deletions covering the N-terminal regions of COL4A5 and COL4A6, which are localized in a head-to-head manner, are found in the chromosome Xq22.3 centromeric deletion syndrome. This results in a phenotype with features of diffuse leiomyomatosis and Alport syndrome (DL-ATS).;

Intolerance Scores

LoFtool
0.00255
RVIS EVS
-1.15
RVIS percentile EVS
6.32

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.222

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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