NOTCH4

protein-coding

notch receptor 4, the group of Notch receptors

Gene summary

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

Previous symbols:

INT3

MANE transcript

NM_004557.4

Inheritance

—

ClinVar variants

U:237B:35

Top phenotype

Congenital heart disease

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr6:32,194,843-32,224,067

External References & Databases

Ensembl (ENSG00000204301)

Transcript & Mutation Effects

hg38 • Region Span ~29.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NOTCH4 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 223

not providedTotal: 37

Congenital heart diseaseTotal: 1

Congenital anomaly of kidney and urinary tractTotal: 1

Anophthalmia-microphthalmia syndromeTotal: 1

Aganglionic megacolonTotal: 1

Cerebral arteriovenous malformationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004557.4. 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			3 clinvar	9 clinvar	9 clinvar	21
missense			229 clinvar	12 clinvar	5 clinvar	246
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	237	21	14	272

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004557.4	RefSeq	NP_004548.3	30	MANE Select
ENST00000375023.3	Ensembl	ENSP00000364163.3	30	MANE Select
ENST00000883244.1	Ensembl	ENSP00000553303.1	30	Standard
ENST00000883245.1	Ensembl	ENSP00000553304.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Breast cancer - Homo sapiens (human)
Thyroid hormone signaling pathway - Homo sapiens (human)
MicroRNAs in cancer - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Notch signaling pathway - Homo sapiens (human)

Biological Process

branching involved in blood vessel morphogenesis
cell fate determination
morphogenesis of a branching structure
endothelial cell morphogenesis
vasculature development

Molecular Function

calcium ion binding
protein binding
signaling receptor activity
protein heterodimerization activity

Cellular Component

Golgi membrane
extracellular region
nucleus
nucleoplasm
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375023
Coding exons: 30
Length: 29225
Individuals with no LoFs: 125564
Homozygous LoFs: 0
Heterozygous LoFs: 184
Defined: 125748
p: 0.000732

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	937	1.14e+3	0.822	0.0000616	12764
Missense (PolyPhen)		379	460.99	0.82215		5314
Synonymous	3.02	378	460	0.821	0.0000252	4191
Loss of Function	3.56	51	86.8	0.588	0.00000432	977

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.00098	notable
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00083	0.00082	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00066	0.00062	rare
South Asian	0.0011	0.0010	notable
Other	0.00067	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. May regulate branching morphogenesis in the developing vascular system (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.138
RVIS EVS: 0.15
RVIS percentile EVS: 64.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.946

Gene Damage Prediction

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