EGF

protein-coding

epidermal growth factor

Gene summary

This gene encodes a member of the epidermal growth factor superfamily. The encoded preproprotein is proteolytically processed to generate the 53-amino acid epidermal growth factor peptide. This protein acts a potent mitogenic factor that plays an important role in the growth, proliferation and differentiation of numerous cell types. This protein acts by binding with high affinity to the cell surface receptor, epidermal growth factor receptor. Defects in this gene are the cause of hypomagnesemia type 4. Dysregulation of this gene has been associated with the growth and progression of certain cancers. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

MANE transcript

NM_001963.6

Inheritance

AD, AR

ClinVar variants

P:4U:284B:121

Top phenotype

Hypomagnesemia 4, renal

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr4:109,912,883-110,013,766

External References & Databases

Ensembl (ENSG00000138798)

Transcript & Mutation Effects

hg38 • Region Span ~100.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal hypomagnesemia 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012717

Submitter: Ambry Genetics

renal hypomagnesemia 4LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012717

Submitter: ClinGen

EGF was first reported in relation to autosomal recessive Renal Hypomagnesemia 4 in 2007 (Groenestege et al., PMID: 17671655). The disease has symptoms of small serum magnesium concentrations, reduced urinary tubular magnesium reuptake, seizures, and moderately inhibited intellectual development. One variant (missense) that has been reported in two probands from one family in one publication (PMID: 17671655) is included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence. For instance, GTEx expression data shows high expression in the medulla and cortex of kidney. Also, functional evidence demonstrates reduced renal magnesium channel activity associated with inhibiting EGFR, the receptor of EGF (PMID: 17671655). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 10/19/2023 (SOP Version 9).

renal hypomagnesemia 4LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012717

Submitter: PanelApp Australia

renal hypomagnesemia 4LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012717

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hypomagnesemia 4, renalAR

Manifestation: Renal

Intervention: Renal

Rationale: Children may present with tetany and/or convulsions, and failure of early diagnosis (or treatment noncompliance) can be fatal or result in permanent neurological damage due to electrolyte abnormalities; Replacement therapy may be beneficial

Refs: 3436090; 17671655

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EGF variants in ClinVar

6 Conditions Cataloged

not providedTotal: 422

not specifiedTotal: 150

Renal hypomagnesemia 4Total: 93

EGF-related disorderTotal: 27

EGF-related disordersTotal: 1

Hereditary renal cell carcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001963.6. 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	89 clinvar	2 clinvar	97
missense	1 clinvar		250 clinvar	25 clinvar	3 clinvar	279
nonsense			17 clinvar	1 clinvar		18
start loss			1 clinvar			1
frameshift			5 clinvar		1 clinvar	6
splice donor/acceptor (+/-2bp)		3 clinvar	5 clinvar			8
Total	1	3	284	115	6	409

Highest pathogenic variant AF is 0.000011774607

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_001963.6	RefSeq	NP_001954.2	24	MANE Select
ENST00000265171.10	Ensembl	ENSP00000265171.5	24	MANE Select
NM_001178130.3	RefSeq	NP_001171601.1	23	Standard
NM_001178131.3	RefSeq	NP_001171602.1	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
egf	Danio rerio	Structure: dorsal longitudinal anastomotic vessel Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

egf

Danio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Choline metabolism in cancer - Homo sapiens (human)

Biological Process

MAPK cascade
activation of MAPKK activity
activation of MAPK activity
angiogenesis
positive regulation of receptor internalization

Molecular Function

protein tyrosine kinase activity
Ras guanyl-nucleotide exchange factor activity
epidermal growth factor receptor binding
calcium ion binding
protein binding

Cellular Component

extracellular region
extracellular space
lysosomal membrane
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265171
Coding exons: 24
Length: 99383
Individuals with no LoFs: 125629
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125748
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.938	571	638	0.895	0.0000338	7919
Missense (PolyPhen)		129	176.13	0.73241		2235
Synonymous	-0.775	241	226	1.07	0.0000119	2277
Loss of Function	3.29	37	65.8	0.563	0.00000383	761

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00092	0.00092	rare
Latino/Admixed American	0.00075	0.00075	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00071	0.00071	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00056	0.00056	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture. Magnesiotropic hormone that stimulates magnesium reabsorption in the renal distal convoluted tubule via engagement of EGFR and activation of the magnesium channel TRPM6. Can induce neurite outgrowth in motoneurons of the pond snail Lymnaea stagnalis in vitro (PubMed:10964941). {ECO:0000269|PubMed:10964941, ECO:0000269|PubMed:17671655}.;
Disease: DISEASE: Hypomagnesemia 4 (HOMG4) [MIM:611718]: A disorder characterized by massive renal hypomagnesemia and normal levels of serum calcium and calcium excretion. Clinical features include seizures, mild-to moderate psychomotor retardation, and brisk tendon reflexes. {ECO:0000269|PubMed:17671655}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.973

Intolerance Scores

LoFtool: 0.0495
RVIS EVS: 1.3
RVIS percentile EVS: 93.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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