MEGF8

protein-coding

multiple EGF like domains 8, the group of MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

Previous symbols:

EGFL4
C19orf49

MANE transcript

NM_001271938.2

Inheritance

ClinVar variants

P:40U:648B:393

Top phenotype

Carpenter syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr19:42,325,609-42,378,769

External References & Databases

Ensembl (ENSG00000105429)

Transcript & Mutation Effects

hg38 • Region Span ~53.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MEGF8-related Carpenter syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013998

Submitter: Labcorp Genetics (formerly Invitae)

MEGF8-related Carpenter syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013998

Submitter: PanelApp Australia

MEGF8-related Carpenter syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013998

Submitter: Ambry Genetics

MEGF8-related Carpenter syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013998

Submitter: ClinGen

MEGF8 was first reported in relation to autosomal recessive Carpenter syndrome as early as 2012 (Twigg et al., PMID: 23063620). At least six different variants (missense, nonsense, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes six variants described in four probands in one publication (PMID: 23063620). In addition, we included one internal case, a proband with Carpenter syndrome who was compound heterozygous for c.4872delG (p.Phe1625Serfs) and c.7769_7771delCCT (p.Ser2590del), to reach a score of 6 points for genetic evidence. The mechanism of disease is proposed to be partial loss of function (PMID: 26340332). This gene-disease relationship is also supported by mouse models, expression data, and in vitro functional assays (PMID: 19218456, 23063620, 24052814, 32203821, 32966817). In summary, there is moderate evidence to support the relationship between MEGF8 and autosomal recessive Carpenter syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This curation was approved by the Craniofacial Malformations Gene Curation Expert Panel on 6/17/21 (SOP Version 8).

MEGF8-related Carpenter syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013998

Submitter: G2P

Carpenter syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019012

Submitter: Orphanet

Clinical Genomic Database (CGD)

Carpenter syndrome 2AR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Genitourinary; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 23063620

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MEGF8 variants in ClinVar

8 Conditions Cataloged

MEGF8-related Carpenter syndromeTotal: 688

Inborn genetic diseasesTotal: 444

not providedTotal: 279

not specifiedTotal: 170

MEGF8-related disorderTotal: 59

Carpenter syndromeTotal: 3

Craniosynostosis syndromeTotal: 1

PolydactylyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001271938.2. 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			11 clinvar	334 clinvar	10 clinvar	355
missense	2 clinvar	3 clinvar	619 clinvar	47 clinvar	2 clinvar	673
nonsense	7 clinvar	8 clinvar	5 clinvar			20
start loss						0
frameshift	7 clinvar	3 clinvar				10
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	13 clinvar			23
Total	18	22	648	381	12	1081

Highest pathogenic variant AF is 0.000022992277

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001271938.2	RefSeq	NP_001258867.1	42	MANE Select
ENST00000251268.11	Ensembl	ENSP00000251268.5	42	MANE Select
NM_001410.3	RefSeq	NP_001401.2	41	Standard
ENST00000334370.8	Ensembl	ENSP00000334219.4	41	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
megf8	Danio rerio	Structure: heart tube Quality: position abnormal

Gene / Model

Organism

Observed Phenotype

megf8

Danio rerio

Structure: heart tube

Quality: position

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

embryonic heart tube morphogenesis
regulation of gene expression
embryonic limb morphogenesis
BMP signaling pathway
limb morphogenesis

Molecular Function

calcium ion binding
protein binding

Cellular Component

nucleus
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334370
Coding exons: 41
Length: 53161
Individuals with no LoFs: 125530
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125594
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.48	1304	1.71e+3	0.763	0.000115	17464
Missense (PolyPhen)		338	566.73	0.5964		6006
Synonymous	0.768	704	730	0.964	0.0000510	5903
Loss of Function	7.56	35	127	0.276	0.00000693	1306

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00030	0.00025	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00015	0.00014	rare
European (Non-Finnish)	0.00033	0.00031	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a negative regulator of hedgehog signaling. {ECO:0000250|UniProtKB:P60882}.;
Disease: DISEASE: Carpenter syndrome 2 (CRPT2) [MIM:614976]: An autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease. {ECO:0000269|PubMed:23063620}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.696
RVIS EVS: -4.01
RVIS percentile EVS: 0.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.940

Gene Damage Prediction

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