MEGF10

protein-coding

multiple EGF like domains 10, the group of Scavenger receptors

Gene summary

This gene encodes a member of the multiple epidermal growth factor-like domains protein family. The encoded protein plays a role in cell adhesion, motility and proliferation, and is a critical mediator of apoptotic cell phagocytosis as well as amyloid-beta peptide uptake in the brain. Expression of this gene may be associated with schizophrenia, and mutations in this gene are a cause of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) as well as congenital myopathy with minicores. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

MANE transcript

NM_001256545.2

Inheritance

ClinVar variants

P:71U:485B:234

Top phenotype

Congenital myopathy 10A, severe variant; Congenital myopathy 10B, mild variant

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr5:127,290,796-127,465,737

External References & Databases

Ensembl (ENSG00000145794)

Transcript & Mutation Effects

hg38 • Region Span ~174.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MEGF10-related myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013731

Submitter: Labcorp Genetics (formerly Invitae)

MEGF10-related myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013731

Submitter: G2P

MEGF10-related myopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013731

Submitter: Orphanet

MEGF10-related myopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013731

Submitter: ClinGen

MEGF10 was first reported in relation to autosomal recessive MEGF10-related myopathy, historically known as early-onset myopathy-areflexia-respiratory distress-dysphagia (EMARDD) in 2011 (Logan et al., PMID: 22101682). At least 11 variants (e.g. missense, nonsense, frameshift, deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least nine probands in four publications (PMIDs: 22101682, 22371254, 23453856, 27460346). Variants in this gene segregated with disease in two additional family members plus several sibling pairs. More evidence is available in the literature, but the maximum score for genetic evidence has been reached.The mechanism for disease is homozygous loss of function, with MEGF10 deficency reducing the proliferation and migration of muscle sattelite cells, impeding muscle repair, and supporting premature differentiation in myoblasts during development. Of note, this gene has also been implicated in a form of multiminicore myopathy with generally reduced phenotypic severity and later age of onset. This entity is considered part of the MEGF10-related myopathy spectrum. This gene-disease association is supported by two animal models, expression studies, biochemical function evidence, and myoblast alteration. Models in both zebrafish and mice displayed some phenotypes of MEGF10 myopathy, but were ultimately limited in scope. Expression data showed clear expression in myoblasts during development and sattelite cells in mature organisms further supporting the disease mechanism. Biochemical function studies demonstrated the MEGF10 pathogenic mechanism. Mouse myoblasts were altered and found to have reduced migration, proliferation, and premature differentiation in the absence of MEFG10. In summary, MEGF10 is definitively associated with autosomal recessive MEGF10-related myopathy. This has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies Working Group on 01/27/20 (SOP Version 7).

MEGF10-related myopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013731

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Congenital myopathy 10A, severe variant; Congenital myopathy 10B, mild variantAR

Manifestation: 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: 17236770; 22101682; 22371254; 23453856; 27460346; 36349186

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MEGF10 variants in ClinVar

8 Conditions Cataloged

MEGF10-related myopathyTotal: 815

not providedTotal: 220

Inborn genetic diseasesTotal: 168

not specifiedTotal: 72

MEGF10-related disorderTotal: 27

Congenital myopathy 10b, mild variantTotal: 21

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

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001256545.2. 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	212 clinvar	2 clinvar	219
missense	3 clinvar	6 clinvar	474 clinvar	20 clinvar		503
nonsense	18 clinvar	6 clinvar				24
start loss			1 clinvar			1
frameshift	11 clinvar	7 clinvar	1 clinvar			19
splice donor/acceptor (+/-2bp)	2 clinvar	18 clinvar	4 clinvar			24
Total	34	37	485	232	2	790

Highest pathogenic variant AF is 0.00012268235

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001256545.2	RefSeq	NP_001243474.1	24	MANE Select
ENST00000503335.7	Ensembl	ENSP00000423354.2	24	MANE Select
NM_001308119.2	RefSeq	NP_001295048.1	13	Standard
NM_001308121.2	RefSeq	NP_001295050.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
megf10	Danio rerio	Structure: muscle Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

megf10

Danio rerio

Structure: muscle

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

receptor-mediated endocytosis
skeletal muscle satellite cell activation
skeletal muscle satellite cell differentiation
skeletal muscle satellite cell proliferation
muscle cell proliferation

Molecular Function

complement component C1q binding
scavenger receptor activity
Notch binding

Cellular Component

phagocytic cup
plasma membrane
integral component of membrane
cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274473
Coding exons: 24
Length: 174907
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 74
Defined: 125748
p: 0.000294

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	608	685	0.887	0.0000394	7497
Missense (PolyPhen)		187	259.05	0.72187		2798
Synonymous	0.758	239	254	0.940	0.0000162	2096
Loss of Function	5.85	15	66.5	0.226	0.00000344	766

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0011	0.0011	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00030	0.00029	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Membrane receptor involved in phagocytosis by macrophages and astrocytes of apoptotic cells. Receptor for C1q, an eat-me signal, that binds phosphatidylserine expressed on the surface of apoptotic cells (PubMed:27170117). Cooperates with ABCA1 within the process of engulfment. Promotes the formation of large intracellular vacuoles and may be responsible for the uptake of amyloid-beta peptides (PubMed:20828568, PubMed:17643423). Necessary for astrocyte-dependent apoptotic neuron clearance in the developing cerebellum (PubMed:27170117). Plays role in muscle cell proliferation, adhesion and motility. Is also an essential factor in the regulation of myogenesis. Controls the balance between skeletal muscle satellite cells proliferation and differentiation through regulation of the notch signaling pathway (PubMed:28498977). May also function in the mosaic spacing of specific neuron subtypes in the retina through homotypic retinal neuron repulsion. Mosaics provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements (PubMed:17498693, PubMed:17643423, PubMed:20828568, PubMed:22101682, PubMed:27170117, PubMed:28498977). {ECO:0000269|PubMed:17205124, ECO:0000269|PubMed:17498693, ECO:0000269|PubMed:17643423, ECO:0000269|PubMed:20828568, ECO:0000269|PubMed:22101682, ECO:0000269|PubMed:27170117, ECO:0000269|PubMed:28498977}.;
Disease: DISEASE: Myopathy, early-onset, areflexia, respiratory distress, and dysphagia (EMARDD) [MIM:614399]: An autosomal recessive congenital myopathy characterized by onset at birth, or early in infancy, of respiratory distress caused by diaphragmatic weakness. Additional features are dysphagia resulting in poor feeding, failure to thrive, poor head control, facial weakness, cleft palate, contractures and scoliosis. Affected individuals become ventilator-dependent, and most require feeding by gastrostomy. The disorder results in severe muscle weakness and most patients never achieve walking. Death from respiratory failure in childhood occurs in about half of patients. Muscle biopsies from affected individuals show myopathic changes, replacement of myofibers with fatty tissue, small and incompletely fused muscle fibers, and variation in fiber size. Short regions of sarcomeric disorganization with few or no mitochondria (minicores) have been observed in some cases. {ECO:0000269|PubMed:22101682, ECO:0000269|PubMed:22371254, ECO:0000269|PubMed:23954233, ECO:0000269|PubMed:27170117, ECO:0000269|PubMed:28498977}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.124

Intolerance Scores

LoFtool: 0.476
RVIS EVS: -1.21
RVIS percentile EVS: 5.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.262

Gene Damage Prediction

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