MATN3

protein-coding

matrilin 3, the group of Matrilins

Gene summary

This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002381.5

Inheritance

AD, AR

ClinVar variants

P:14U:220B:88

Top phenotype

Epiphyseal dysplasia, multiple, 5; Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr2:19,992,052-20,012,668

External References & Databases

Ensembl (ENSG00000132031)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple epiphyseal dysplasia type 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011765

Submitter: G2P

multiple epiphyseal dysplasia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011765

Submitter: PanelApp Australia

spondyloepimetaphyseal dysplasia, matrilin-3 typeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012108

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, matrilin-3 typeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012108

Submitter: Ambry Genetics

multiple epiphyseal dysplasia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011765

Submitter: Ambry Genetics

multiple epiphyseal dysplasia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011765

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, matrilin-3 typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012108

Submitter: PanelApp Australia

multiple epiphyseal dysplasia type 5SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011765

Submitter: Orphanet

spondyloepimetaphyseal dysplasia, matrilin-3 typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012108

Submitter: Orphanet

Clinical Genomic Database (CGD)

Epiphyseal dysplasia, multiple, 5; Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire typeAD/AR

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: 13849708; 11479597; 11528506; 12884427; 15121775; 14729835; 15948199; 18205203; 20301302; 21922596; 21965141

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MATN3 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 277

Inborn genetic diseasesTotal: 69

Multiple epiphyseal dysplasia type 5Total: 65

not specifiedTotal: 25

MATN3-related disorderTotal: 17

Multiple epiphyseal dysplasiaTotal: 15

Spondyloepimetaphyseal dysplasia, matrilin-3 typeTotal: 15

Osteoarthritis susceptibility 2Total: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002381.5. 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			6 clinvar	66 clinvar	1 clinvar	73
missense	3 clinvar	10 clinvar	190 clinvar	19 clinvar	2 clinvar	224
nonsense		1 clinvar	7 clinvar			8
start loss			1 clinvar			1
frameshift			12 clinvar			12
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	3	11	220	85	3	322

Highest pathogenic variant AF is 0.000014871455

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_002381.5	RefSeq	NP_002372.1	8	MANE Select
ENST00000407540.8	Ensembl	ENSP00000383894.3	8	MANE Select
ENST00000421259.2	Ensembl	ENSP00000398753.2	7	Standard
ENST00000421259.3	Ensembl	ENSP00000398753.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins
Extracellular matrix organization
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

Biological Process

skeletal system development
growth plate cartilage chondrocyte morphogenesis
extracellular matrix organization
post-translational protein modification
cellular protein metabolic process

Molecular Function

extracellular matrix structural constituent
calcium ion binding
protein binding

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000407540
Coding exons: 8
Length: 20584
Individuals with no LoFs: 124599
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 124646
p: 0.000189

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.771	201	234	0.858	0.0000129	3125
Missense (PolyPhen)		84	106.12	0.79156		1237
Synonymous	1.10	76	89.2	0.852	0.00000509	986
Loss of Function	0.779	14	17.5	0.799	9.63e-7	239

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00052	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00053	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.;
Disease: DISEASE: Spondyloepimetaphyseal dysplasia MATN3-related (SEMD- MATN3) [MIM:608728]: A bone disease characterized by disproportionate early-onset dwarfism, bowing of the lower limbs, lumbar lordosis and normal hands. Skeletal abnormalities include short, wide and stocky long bones with severe epiphyseal and metaphyseal changes, hypoplastic iliac bones and flat, ovoid vertebral bodies. {ECO:0000269|PubMed:15121775}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteoarthritis 2 (OS2) [MIM:140600]: A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. In the hand, osteoarthritis can develop in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints. Patients with osteoarthritis may have one, a few, or all of these sites affected. {ECO:0000269|PubMed:12736871}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.129

Intolerance Scores

RVIS EVS: 0.49
RVIS percentile EVS: 79.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.564

Gene Damage Prediction

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