MMP14

protein-coding

matrix metallopeptidase 14, 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. However, the protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily; each member of this subfamily contains a potential transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. This protein activates MMP2 protein, and this activity may be involved in tumor invasion. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004995.4

Inheritance

ClinVar variants

P:2U:204B:92

Top phenotype

Winchester syndrome

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr14:22,836,560-22,849,041

External References & Databases

Ensembl (ENSG00000157227)

Transcript & Mutation Effects

hg38 • Region Span ~12.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Winchester syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0010201

Submitter: G2P

Winchester syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010201

Submitter: Labcorp Genetics (formerly Invitae)

multicentric osteolysis-nodulosis-arthropathy spectrumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018298

Submitter: Orphanet

Winchester syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010201

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Winchester syndromeAR

Manifestation: Biochemical; Craniofacial; 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: 4238825; 22922033

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MMP14 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 297

Inborn genetic diseasesTotal: 80

Winchester syndromeTotal: 5

MMP14-related disorderTotal: 3

not specifiedTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004995.4. 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 clinvar	80 clinvar	4 clinvar	87
missense	2 clinvar		194 clinvar	5 clinvar	3 clinvar	204
nonsense			3 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	0	204	85	7	298

Highest pathogenic variant AF is 0.000004104287

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004995.4	RefSeq	NP_004986.1	10	MANE Select
ENST00000311852.11	Ensembl	ENSP00000308208.6	10	MANE Select
ENST00000547279.1	Ensembl	ENSP00000450323.1	2	Standard
ENST00000548162.2	Ensembl	ENSP00000506068.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mmp14b	Danio rerio	Structure: auditory capsule Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

mmp14b

Danio rerio

Structure: auditory capsule

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GnRH signaling pathway - Homo sapiens (human)
TNF signaling pathway - Homo sapiens (human)
Matrix Metalloproteinases
Angiogenesis overview
AGE-RAGE pathway

Biological Process

skeletal system development
angiogenesis
ovarian follicle development
response to hypoxia
endothelial cell proliferation

Molecular Function

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

Cellular Component

extracellular space
nucleus
cytoplasm
Golgi lumen
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311852
Coding exons: 10
Length: 12471
Individuals with no LoFs: 125458
Homozygous LoFs: 0
Heterozygous LoFs: 290
Defined: 125748
p: 0.00115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	290	370	0.783	0.0000229	3797
Missense (PolyPhen)		109	171.81	0.63441		1736
Synonymous	0.244	152	156	0.975	0.0000107	1153
Loss of Function	4.48	3	29.1	0.103	0.00000156	299

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0013	0.0012	notable
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0053	0.0053	notable
Finnish	0.0015	0.0014	notable
European (Non-Finnish)	0.0010	0.0010	notable
South Asian	0.00026	0.00026	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Endopeptidase that degrades various components of the extracellular matrix such as collagen. Activates progelatinase A. Essential for pericellular collagenolysis and modeling of skeletal and extraskeletal connective tissues during development (By similarity). May be involved in actin cytoskeleton reorganization by cleaving PTK7 (PubMed:20837484). Acts as a positive regulator of cell growth and migration via activation of MMP15. Involved in the formation of the fibrovascular tissues in association with pro-MMP2 (PubMed:12714657). Cleaves ADGRB1 to release vasculostatin-40 which inhibits angiogenesis (PubMed:22330140). {ECO:0000250|UniProtKB:P53690, ECO:0000269|PubMed:12714657, ECO:0000269|PubMed:20837484, ECO:0000269|PubMed:22065321, ECO:0000269|PubMed:22330140}.;
Disease: DISEASE: Winchester syndrome (WNCHRS) [MIM:277950]: A disease characterized by severe osteolysis in the hands and feet, generalized osteoporosis, bone thinning, and absence of subcutaneous nodules. Various additional features include coarse face, corneal opacities, gum hypertrophy, and EKG changes. {ECO:0000269|PubMed:22922033}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.557

Intolerance Scores

LoFtool: 0.0497
RVIS EVS: 0.05
RVIS percentile EVS: 57.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.587

Gene Damage Prediction

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