COL4A6
protein-codingcollagen type IV alpha 6 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. 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, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~283.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010706
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010484
Submitter: ClinGen
COL4A6 was first reported in relation to X-linked deafness in 2014 (Rost et al., PMID: 23714752).1 variant (missense) has been reported in 1 proband in the 1 publication (PMID: 23714752) included in this curation. This variant was reported to segregate with the disease in 3 additional family members. The mechanism of pathogenicity appears to be dominant-negative. COL4A6 knockout mice have been shown to have similar click-evoked auditory brainstem response, expression of major basement membrane components, and cochlear structures of COL4A6 to WT mice. (PMID: 33848312). Of note, this gene has also been implicated in chronic kidney disease, premature ovarian failure, and diffuse leiomyomatosis in Alport syndrome, and will be assessed separately. This gene-disease association is also supported by expression studies (PMID: 23714752). Immunohistochemical staining of the mouse inner ear with a COL4A6-specific antibody showed pronounced COL4A6 signals at stria vascularis of spiral ligament. Additionally, whole-mount in situ hybridization detected COL4A6 homologs in dorsal midbrain, notochord, and otic vesicle of zebrafish embryos. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 1/16/2018. It was re-evaluated on 2/16/2022. As a result of this reevaluation, the classification did not change, and no new additional information was added to the curation.
Inheritance Pattern: XL
Disease ID:MONDO:0010484
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0019586
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010484
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic
Intervention: Audiologic/Otolaryngologic
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COL4A6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_033641.4. 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 | 38 | 141 | 9 | 188 | ||
| missense | 3 | 401 | 61 | 1 | 466 | |
| nonsense | 17 | 17 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 4 | |||
| splice donor/acceptor (+/-2bp) | 50 | 50 | ||||
| Total | 0 | 4 | 509 | 202 | 10 | 725 |
Highest pathogenic variant AF is 0.00002148595
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_378667.1 | 45 | MANE Select | |
| Ensembl | ENSP00000334733.7 | 45 | MANE Select | |
| RefSeq | NP_001274687.1 | 46 | Standard | |
| RefSeq | NP_001274688.1 | 44 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| col4a6 | Danio 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
- cell adhesion
- 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:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372216
- Coding exons
- 45
- Length
- 295948
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 7
- Heterozygous LoFs
- 17
- Defined
- 125741
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.48 | 538 | 644 | 0.836 | 0.0000477 | 10531 |
| Missense (PolyPhen) | 141 | 207.79 | 0.67857 | 3327 | ||
| Synonymous | -0.230 | 246 | 241 | 1.02 | 0.0000188 | 3812 |
| Loss of Function | 5.76 | 12 | 60.3 | 0.199 | 0.00000452 | 1087 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000087 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00013 | 0.000099 | rare |
| East Asian | 0.00050 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00018 | 0.00011 | rare |
| South Asian | 0.00018 | 0.000098 | rare |
| Other | 0.00026 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- 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: 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).; DISEASE: Deafness, X-linked, 6 (DFNX6) [MIM:300914]: A non- syndromic form of sensorineural hearing loss with prelingual onset. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:23714752}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0746
Intolerance Scores
- LoFtool
- 0.0282
- RVIS EVS
- 0.37
- RVIS percentile EVS
- 74.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0121
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |