MMP9

protein-coding

matrix metallopeptidase 9, the group of M10 matrix metallopeptidases

Gene summary

Proteins of the matrix metalloproteinase (MMP) 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. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. The enzyme encoded by this gene degrades type IV and V collagens. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. [provided by RefSeq, Jul 2008]

Previous symbols:

CLG4B

MANE transcript

NM_004994.3

Inheritance

AD, AR

ClinVar variants

P:4U:280B:115

Top phenotype

Metaphyseal anadysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr20:46,008,908-46,016,561

External References & Databases

Ensembl (ENSG00000100985)

Transcript & Mutation Effects

hg38 • Region Span ~7.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

metaphyseal anadysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015177

Submitter: Orphanet

metaphyseal anadysplasia 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013113

Submitter: PanelApp Australia

metaphyseal anadysplasia 2LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013113

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Metaphyseal anadysplasia 2AR

Manifestation: Musculoskeletal

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: 4252978; 1867263; 19615667

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MMP9 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 396

not specifiedTotal: 89

Metaphyseal anadysplasia 2Total: 49

MMP9-related disorderTotal: 6

Mendelian syndromes with cleft lip/palateTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004994.3. 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			5 clinvar	98 clinvar	3 clinvar	106
missense		1 clinvar	253 clinvar	11 clinvar	1 clinvar	266
nonsense		2 clinvar	6 clinvar			8
start loss			1 clinvar			1
frameshift		1 clinvar	7 clinvar	2 clinvar		10
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	4	280	111	4	399

Highest pathogenic variant AF is 0.00005348648

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004994.3	RefSeq	NP_004985.2	13	MANE Select
ENST00000372330.3	Ensembl	ENSP00000361405.3	13	MANE Select
ENST00000898203.1	Ensembl	ENSP00000568262.1	13	Standard
ENST00000898203.2	Ensembl	ENSP00000568262.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mmp9	Danio rerio	Structure: mandibular arch skeleton Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

mmp9

Danio rerio

Structure: mandibular arch skeleton

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Relaxin signaling pathway - Homo sapiens (human)
Bladder cancer - Homo sapiens (human)
TNF signaling pathway - Homo sapiens (human)
Prostate cancer - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)

Biological Process

skeletal system development
ossification
positive regulation of protein phosphorylation
proteolysis
embryo implantation

Molecular Function

endopeptidase activity
metalloendopeptidase activity
serine-type endopeptidase activity
protein binding
collagen binding

Cellular Component

extracellular region
extracellular space
collagen-containing extracellular matrix
extracellular exosome
tertiary granule lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372330
Coding exons: 13
Length: 7654
Individuals with no LoFs: 125514
Homozygous LoFs: 2
Heterozygous LoFs: 232
Defined: 125748
p: 0.000931

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.415	416	441	0.944	0.0000290	4518
Missense (PolyPhen)		144	147.63	0.97539		1572
Synonymous	0.147	196	199	0.987	0.0000152	1452
Loss of Function	0.631	28	31.8	0.879	0.00000148	344

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0.010	0.010	notable
East Asian	0.00076	0.00076	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00074	0.00072	rare
South Asian	0.00046	0.00046	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide. {ECO:0000269|PubMed:1480034}.;
Disease: DISEASE: Intervertebral disc disease (IDD) [MIM:603932]: A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. {ECO:0000269|PubMed:18455130}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Metaphyseal anadysplasia 2 (MANDP2) [MIM:613073]: A bone development disorder characterized by skeletal anomalies that resolve spontaneously with age. Clinical characteristics are evident from the first months of life and include slight shortness of stature and a mild varus deformity of the legs. Patients attain a normal stature in adolescence and show improvement or complete resolution of varus deformity of the legs and rhizomelic micromelia. {ECO:0000269|PubMed:19615667}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.972

Intolerance Scores

LoFtool: 0.926
RVIS EVS: 0.67
RVIS percentile EVS: 84.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.556

Gene Damage Prediction

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