NOTCH4

notch receptor 4, the group of Notch receptors

Basic information

Region (hg38): 6:32194842-32224067

Previous symbols: [ "INT3" ]

Links

ENSG00000204301 ∙ NCBI:4855 ∙ OMIM:164951 ∙ HGNC:7884 ∙ Uniprot:Q99466 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NOTCH4 gene.

• not provided (95 variants)
• Inborn genetic diseases (68 variants)
• not specified (2 variants)
• Anophthalmia-microphthalmia syndrome (1 variants)
• Cerebral arteriovenous malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NOTCH4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				5	20	25
missense			66	6	9	81
nonsense			1			1
start loss						0
frameshift						0
inframe indel				1	4	5
splice donor/acceptor (+/-2bp)						0
splice region				3	2	5
non coding					46	46
Total	0	0	67	12	79

Variants in NOTCH4

This is a list of pathogenic ClinVar variants found in the NOTCH4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-32195497-G-A			Benign (May 05, 2021)
6-32195529-G-A		not specified	Uncertain significance (Oct 06, 2021)
6-32195532-T-A		not specified	Uncertain significance (Jul 19, 2023)
6-32195631-G-A		not specified	Uncertain significance (Feb 06, 2024)
6-32195699-G-A		not specified	Uncertain significance (Jan 26, 2022)
6-32195711-C-G		not specified	Uncertain significance (Aug 09, 2021)
6-32195753-C-G		not specified	Uncertain significance (May 31, 2023)
6-32195756-C-T		not specified	Uncertain significance (Aug 08, 2022)
6-32195764-A-C			Benign (May 05, 2021)
6-32195837-C-T		not specified	Uncertain significance (Aug 11, 2022)
6-32195887-C-T			Benign (May 05, 2021)
6-32195901-C-A		not specified	Uncertain significance (Jan 16, 2024)
6-32195952-G-T		not specified	Uncertain significance (Nov 01, 2021)
6-32195985-C-T		not specified	Uncertain significance (Jul 07, 2022)
6-32196022-T-C			Benign (May 05, 2021)
6-32196153-G-C			Likely benign (May 07, 2018)
6-32196888-CT-C			Benign (May 14, 2021)
6-32196982-C-T		not specified	Uncertain significance (Dec 15, 2022)
6-32197022-C-T			Benign (Apr 24, 2018)
6-32197042-C-T			Likely benign (Jul 23, 2018)
6-32197063-G-A		not specified	Uncertain significance (Jan 18, 2022)
6-32197066-G-A		not specified	Uncertain significance (Sep 14, 2022)
6-32197092-G-C			Benign (May 13, 2021)
6-32197097-C-A			Benign (May 13, 2021)
6-32197424-G-A			Uncertain significance (Jan 05, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NOTCH4	protein_coding	protein_coding	ENST00000375023	30	29225

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.05e-23	1.00	125564	0	184	125748	0.000732

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.14	937	1.14e+3	0.822	0.0000616	12764
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00220	0.00213
Ashkenazi Jewish	0.000303	0.000298
East Asian	0.000827	0.000816
Finnish	0.000243	0.000231
European (Non-Finnish)	0.000660	0.000615
Middle Eastern	0.000827	0.000816
South Asian	0.00107	0.00105
Other	0.000671	0.000652

dbNSFP

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}.
• Pathway: 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);Human papillomavirus infection - Homo sapiens (human);NOTCH-Ncore;Neural Crest Differentiation;Notch Signaling Pathway;Canonical and Non-canonical Notch signaling;VEGFA-VEGFR2 Signaling Pathway;Role of Osx and miRNAs in tooth development;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch-HLH transcription pathway;Notch;NICD traffics to nucleus;Pre-NOTCH Processing in the Endoplasmic Reticulum;Pre-NOTCH Processing in Golgi;Pre-NOTCH Expression and Processing;Signaling by NOTCH4;Signaling by NOTCH;A third proteolytic cleavage releases NICD;Notch signaling pathway (Consensus)

Intolerance Scores

• loftool: 0.138
• rvis_EVS: 0.15
• rvis_percentile_EVS: 64.33

Haploinsufficiency Scores

• pHI: 0.374
• hipred: Y
• hipred_score: 0.595
• ghis: 0.499

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.946

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Notch4
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; embryo phenotype; normal phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); homeostasis/metabolism phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: branching involved in blood vessel morphogenesis;cell fate determination;morphogenesis of a branching structure;endothelial cell morphogenesis;vasculature development;transcription initiation from RNA polymerase II promoter;positive regulation of transcription of Notch receptor target;hemopoiesis;cell differentiation;mammary gland development;miRNA mediated inhibition of translation;wound healing;negative regulation of cell differentiation;negative regulation of endothelial cell differentiation;positive regulation of Notch signaling pathway;positive regulation of transcription, DNA-templated
• Cellular component: Golgi membrane;extracellular region;nucleus;nucleoplasm;endoplasmic reticulum membrane;cytosol;plasma membrane;integral component of plasma membrane;cell surface
• Molecular function: calcium ion binding;protein binding;signaling receptor activity;protein heterodimerization activity