MMP15
protein-codingmatrix metallopeptidase 15, the group of M10 matrix metallopeptidases
Gene summary
This gene encodes a member of the peptidase M10 family and membrane-type subfamily of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Members of this subfamily contain a transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. The encoded preproprotein is proteolytically processed to generate the mature protease. This protein may play a role in cancer progression. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019042
Submitter: LiferaOmics
Genetic evidence – Published PMID: 33875846 – Reports three affected individuals from two unrelated families. Family 1- Two affected siblings Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = 1.0; Segregation (additional affected sibling counted conservatively) = 0.5; Case-control = 0 Family 1 total = 1.5 Family 2 – One affected individual. Case-level (non-LOF start 1.0; homozygous scored once; consanguinity) = 0.1; Segregation = 0; Case-control = 0 Family 2 total = 0.1 PMID: 33875846 total = 1.6 PMID: 34988996 – Reports the same core evidence: two siblings with the homozygous frameshift c.1058delC (p.Pro353Glnfs*102) and references an additional homozygous missense case with similar phenotype. This publication provides supportive functional/interpretive data but does not add new independent families beyond those already captured in PMID33875846, so no additional genetic points are added (to avoid double counting). PMID: 34988996 total = 0 (no new independent genetic evidence) Published genetic evidence total = 1.6 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = 1.0; Segregation = 0 (sibling reportedly died with cardiac anomalies but untested/not genotyped → not scorable); Case-control = 0 Family 1 total = 1.0 Transparency note (phenotype attribution): cholestasis in this proband has a strong alternative molecular explanation (ABCC2, Dubin–Johnson syndrome), so the MMP15 case contribution is anchored primarily on the congenital heart defect + multisystem congenital anomalies overlap with published MMP15 cases; the cholestasis feature is considered confounded in this individual. Our cases total = 1.0 / 12 Total genetic evidence (published + our cases) 1.6 + 1.0 = 2.6 / 12 Experimental evidence – Published PMID: 34988996 – Functional/variant-level support consistent with loss of function: Relative quantification shows degradation of the frameshift transcript consistent with nonsense-mediated decay (supports LoF). Functional alteration (patient RNA / transcript evidence) = 1.0 PMID: 33875846 – Biological plausibility: Mmp15 implicated in endocardial cushion development (mechanistic plausibility for CHD), discussed in the MMP15 section. Gene function / biological plausibility = 0.5 Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 2.6 Experimental evidence = 1.5 Overall score = 4.1
Inheritance Pattern: AR
Disease ID:MONDO:0007318
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MMP15 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002428.4. 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 | 3 | 2 | 1 | 6 | ||
| missense | 125 | 3 | 128 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 131 | 5 | 1 | 138 |
Highest pathogenic variant AF is 6.8902887e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002419.1 | 10 | MANE Select | |
| Ensembl | ENSP00000219271.3 | 10 | MANE Select | |
| Ensembl | ENSP00000457084.1 | 2 | Standard | |
| Ensembl | ENSP00000577651.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Matrix Metalloproteinases
- EMT transition in Colorectal Cancer
- Collagen degradation
- Extracellular matrix organization
- Activation of Matrix Metalloproteinases
Biological Process
- cellular protein modification process
- proteolysis
- extracellular matrix disassembly
- extracellular matrix organization
- collagen catabolic process
Molecular Function
- metalloendopeptidase activity
- protein binding
- enzyme activator activity
- zinc ion binding
- metalloaminopeptidase activity
Cellular Component
- extracellular space
- plasma membrane
- integral component of plasma membrane
- extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219271
- Coding exons
- 10
- Length
- 21336
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 125746
- p
- 0.0000875
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.33 | 374 | 453 | 0.825 | 0.0000328 | 4289 |
| Missense (PolyPhen) | 104 | 150.54 | 0.69084 | 1281 | ||
| Synonymous | -1.00 | 209 | 191 | 1.09 | 0.0000143 | 1384 |
| Loss of Function | 3.73 | 8 | 30.0 | 0.266 | 0.00000172 | 286 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000083 | 0.000079 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endopeptidase that degrades various components of the extracellular matrix. May activate progelatinase A. {ECO:0000269|PubMed:9461298}.;
Recessive Scores
- pRec
- 0.203
Intolerance Scores
- LoFtool
- 0.521
- RVIS EVS
- -0.66
- RVIS percentile EVS
- 16.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.307
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |