ECM1

protein-coding

extracellular matrix protein 1

Gene summary

This gene encodes a soluble protein that is involved in endochondral bone formation, angiogenesis, and tumor biology. It also interacts with a variety of extracellular and structural proteins, contributing to the maintenance of skin integrity and homeostasis. Mutations in this gene are associated with lipoid proteinosis disorder (also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease) that is characterized by generalized thickening of skin, mucosae and certain viscera. Alternatively spliced transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Feb 2011]

MANE transcript

NM_004425.4

Inheritance

ClinVar variants

P:41U:109B:35

Top phenotype

Lipoid proteinosis

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr1:150,508,062-150,513,789

External References & Databases

Ensembl (ENSG00000143369)

Transcript & Mutation Effects

hg38 • Region Span ~5.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lipoid proteinosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009530

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

lipoid proteinosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009530

Submitter: Orphanet

lipoid proteinosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009530

Submitter: PanelApp Australia

lipoid proteinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009530

Submitter: G2P

lipoid proteinosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009530

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lipoid proteinosisAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Dermatologic; Neurologic; Pulmonary

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: 5002423; 751090; 4087005; 11929856; 12603844; 19519837; 19734986; 21349189; 21791056; 21886756; 22182433

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ECM1 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 97

not providedTotal: 47

Lipid proteinosisTotal: 47

not specifiedTotal: 21

ECM1-related disorderTotal: 14

ECM1-related disordersTotal: 4

AutismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004425.4. 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		1 clinvar	1 clinvar	21 clinvar	2 clinvar	25
missense	1 clinvar	3 clinvar	103 clinvar	8 clinvar	4 clinvar	119
nonsense	9 clinvar	4 clinvar	4 clinvar			17
start loss						0
frameshift	10 clinvar	7 clinvar				17
splice donor/acceptor (+/-2bp)	5 clinvar	1 clinvar	1 clinvar			7
Total	25	16	109	29	6	185

Highest pathogenic variant AF is 0.00012578149

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004425.4	RefSeq	NP_004416.2	10	MANE Select
ENST00000369047.9	Ensembl	ENSP00000358043.4	10	MANE Select
NM_001202858.2	RefSeq	NP_001189787.1	10	Standard
NM_022664.3	RefSeq	NP_073155.2	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet degranulation
Response to elevated platelet cytosolic Ca2+
Platelet activation, signaling and aggregation
Hemostasis

Biological Process

ossification
angiogenesis
positive regulation of endothelial cell proliferation
negative regulation of cytokine-mediated signaling pathway
chondrocyte development

Molecular Function

protease binding
interleukin-2 receptor binding
extracellular matrix structural constituent
protein binding
protein C-terminus binding

Cellular Component

extracellular region
extracellular matrix
platelet dense granule lumen
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369049
Coding exons: 10
Length: 5728
Individuals with no LoFs: 125647
Homozygous LoFs: 0
Heterozygous LoFs: 101
Defined: 125748
p: 0.000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.224	336	325	1.03	0.0000198	3684
Missense (PolyPhen)		118	115.23	1.024		1355
Synonymous	0.0945	121	122	0.989	0.00000628	1155
Loss of Function	1.01	24	30.0	0.801	0.00000192	287

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00020	0.00017	rare
Ashkenazi Jewish	0.00070	0.00069	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00061	0.00054	rare
South Asian	0.00030	0.00029	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in endochondral bone formation as negative regulator of bone mineralization. Stimulates the proliferation of endothelial cells and promotes angiogenesis. Inhibits MMP9 proteolytic activity. {ECO:0000269|PubMed:11165938, ECO:0000269|PubMed:11292659, ECO:0000269|PubMed:16512877}.;

Recessive Scores

pRec: 0.301

Intolerance Scores

LoFtool: 0.427
RVIS EVS: -0.27
RVIS percentile EVS: 34.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0999

Gene Damage Prediction

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