COL4A4

protein-coding

collagen type IV alpha 4 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. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000092.5

Inheritance

AR, AD, SD

ClinVar variants

P:1109U:833B:890

Top phenotype

Alport syndrome 2, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr2:227,002,714-227,164,453

External References & Databases

Ensembl (ENSG00000081052)

Transcript & Mutation Effects

hg38 • Region Span ~161.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive Alport syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive Alport syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: G2P

hematuria, benign familial, 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007709

Submitter: Ambry Genetics

autosomal recessive Alport syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Ambry Genetics

hematuria, benign familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007709

Submitter: Genomics England PanelApp

autosomal dominant Alport syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007086

Submitter: Orphanet

autosomal recessive Alport syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Genomics England PanelApp

autosomal recessive Alport syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Myriad Women's Health

hematuria, benign familial, 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007709

Submitter: Labcorp Genetics (formerly Invitae)

Alport syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018965

Submitter: Natera

Alport syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0018965

Submitter: ClinGen

The *COL4A4* gene is located on chromosome 2 at q36.3 and encodes the protein collagen alpha-4(IV) chain. *COL4A4* was first reported in relation to autosomal recessive Alport Syndrome (OMIM: 203780) in 2 families of a cohort of 7 families with presumed autosomal recessive Alport syndrome (Mochizuki et al 1994, PMID: 7987396). Alport syndrome is characterized by hearing loss, anterior lenticonus, and glomerular basement membrane defects that may progress to end-stage kidney disease. Patients often present with hematuria and worsening proteinuria. Kidney biopsy may identify focal segmental glomerulosclerosis and thin glomerular basement membranes with abnormal ultrastructure. Autosomal dominant inheritance has also been reported, leading to an isolated renal phenotype of hematuria, with or without structural changes and progressive disease course. Case reports of digenic inheritance with *COL4A3* or *COL4A5* variants also exist. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism between the reported disease entities and noted that affected families show phenotypic variability with variable expressivity. Therefore, the following disease entities have been lumped into a single disease entity: Alport syndrome 2, autosomal recessive (OMIM:203780) and Hematuria, benign familial (OMIM:141200). The preferred disease name suggested for this grouping of disorders is ‘Alport Spectrum - *COL4A4*’. Twenty seven pathogenic or likely pathogenic variants that have been reported in 22 probands in 5 publications (PMID: 7987396, PMID:9195222, PMID: 9792860, PMID:11961012, PMID:33532864) are included in this curation. No functional data of these variants were provided in these studies. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by expression (PMID: 10534397, PMID: 24522496, PMID: 31892712), protein interaction (PMID: 24522496) and biochemical studies (PMID: 10534397), and animal models (PMID: 10534397, PMID: 21196518, PMID: 24522496, PMID: 31892712). In summary, *COL4A4* is definitively associated with Alport Spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal recessive Alport syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008762

Submitter: Orphanet

Clinical Genomic Database (CGD)

Alport syndrome 2, autosomal recessiveAD/AR

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

Refs: 7033680; 7987396; 7783412; 8787673; 9195222; 20301386; 22166847; 22237748; 22811928; 22997344

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL4A4 variants in ClinVar

39 Conditions Cataloged

not providedTotal: 2534

Autosomal recessive Alport syndromeTotal: 978

Alport syndromeTotal: 730

Hematuria, benign familial, 1Total: 567

not specifiedTotal: 316

COL4A4-related disorderTotal: 292

Inborn genetic diseasesTotal: 248

Benign familial hematuriaTotal: 190

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000092.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	4 clinvar	26 clinvar	751 clinvar	4 clinvar	786
missense	24 clinvar	422 clinvar	788 clinvar	129 clinvar	6 clinvar	1369
nonsense	57 clinvar	71 clinvar				128
start loss						0
frameshift	188 clinvar	178 clinvar	4 clinvar			370
splice donor/acceptor (+/-2bp)	31 clinvar	133 clinvar	15 clinvar			179
Total	301	808	833	880	10	2832

Highest pathogenic variant AF is 0.00032294216

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000092.5	RefSeq	NP_000083.3	47	MANE Select
ENST00000396625.5	Ensembl	ENSP00000379866.3	47	MANE Select
ENST00000643379.1	Ensembl	ENSP00000494516.1	14	Standard
ENST00000682098.1	Ensembl	ENSP00000508331.1	3	Standard

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

angiogenesis
endothelial cell morphogenesis
extracellular matrix organization
glomerular basement membrane development

Molecular Function

extracellular matrix structural constituent

Cellular Component

extracellular region
collagen type IV trimer
basement membrane
extracellular space
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396625
Coding exons: 47
Length: 161403
Individuals with no LoFs: 124700
Homozygous LoFs: 0
Heterozygous LoFs: 94
Defined: 124794
p: 0.000377

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.02	874	963	0.908	0.0000504	10509
Missense (PolyPhen)		220	244.17	0.90102		2513
Synonymous	-1.18	373	345	1.08	0.0000197	3775
Loss of Function	4.49	40	84.5	0.473	0.00000387	1113

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00053	0.00052	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00028	0.00028	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00047	0.00046	rare
South Asian	0.00046	0.00046	rare
Other	0.00049	0.00049	rare

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, autosomal recessive (APSAR) [MIM:203780]: A syndrome characterized by progressive glomerulonephritis, glomerular basement membrane defects, renal failure, sensorineural deafness and specific eye abnormalities (lenticonous and macular flecks). 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:7987396, ECO:0000269|PubMed:9792860}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hematuria, benign familial (BFH) [MIM:141200]: An autosomal dominant condition characterized by non-progressive isolated microscopic hematuria that does not result in renal failure. It is characterized pathologically by thinning of the glomerular basement membrane. {ECO:0000269|PubMed:11961012, ECO:0000269|PubMed:12631110, ECO:0000269|PubMed:8787673}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.249

Intolerance Scores

LoFtool: 0.0825
RVIS EVS: 1.04
RVIS percentile EVS: 91.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0237

Gene Damage Prediction

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