DLL4

delta like canonical Notch ligand 4

Basic information

Region (hg38): 15:40929340-40939073

Links

ENSG00000128917 ∙ NCBI:54567 ∙ OMIM:605185 ∙ HGNC:2910 ∙ Uniprot:Q9NR61 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Adams-Oliver syndrome 6 (Strong), mode of inheritance: AD
• Adams-Oliver syndrome (Supportive), mode of inheritance: AD
• aplasia cutis congenita (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Adams-Oliver syndrome 6	AD	Cardiovascular	The condition can involve congenital cardiac anomalies, and awareness may allow early management	Cardiovascular; Dermatologic; Musculoskeletal	26299364

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DLL4 gene.

• Adams-Oliver syndrome 6 (10 variants)
• Adams-Oliver syndrome (8 variants)
• not provided (2 variants)
• DLL4-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLL4 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			2	56	8	66
missense	9	7	96	10	2	124
nonsense	3	1				4
start loss						0
frameshift	2	1				3
inframe indel			2			2
splice donor/acceptor (+/-2bp)		1				1
splice region			5	5		10
non coding				26	11	37
Total	14	10	100	92	21

Variants in DLL4

This is a list of pathogenic ClinVar variants found in the DLL4 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-40929564-C-G			Likely benign (Oct 09, 2020)
15-40929673-C-T			Uncertain significance (Jun 03, 2022)
15-40929680-G-A			Likely benign (Oct 03, 2023)
15-40929686-G-A			Likely benign (Nov 14, 2023)
15-40929703-C-T			Uncertain significance (Jul 19, 2022)
15-40929707-A-T		DLL4-related disorder	Benign (Oct 13, 2023)
15-40929723-C-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Apr 12, 2024)
15-40929727-G-T			Uncertain significance (Jun 05, 2022)
15-40929789-C-T			Likely benign (Oct 21, 2019)
15-40929827-C-T			Benign/Likely benign (Jan 22, 2025)
15-40929837-T-C			Likely benign (Jan 31, 2023)
15-40929848-G-A		Inborn genetic diseases	Likely benign (May 28, 2024)
15-40929862-G-C		Adams-Oliver syndrome 6	Likely pathogenic (Dec 18, 2020)
15-40929936-C-T			Likely benign (Jan 15, 2023)
15-40929967-A-G		Adams-Oliver syndrome 6	Likely pathogenic (Nov 17, 2021)
15-40929980-C-T			Uncertain significance (Mar 31, 2022)
15-40929984-C-A			Likely benign (Aug 13, 2022)
15-40929985-G-T		Inborn genetic diseases	Conflicting classifications of pathogenicity (Aug 17, 2023)
15-40930013-C-A			Uncertain significance (May 20, 2023)
15-40930043-CCTT-C		Adams-Oliver syndrome 6	Uncertain significance (Dec 01, 2017)
15-40930073-G-C		Inborn genetic diseases	Uncertain significance (Dec 15, 2022)
15-40930077-G-C			Likely benign (Aug 17, 2023)
15-40930085-C-A			Uncertain significance (Sep 19, 2022)
15-40930095-G-A			Likely benign (Mar 26, 2022)
15-40930109-C-T		Adams-Oliver syndrome 6	Likely pathogenic (Jul 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLL4	protein_coding	protein_coding	ENST00000249749	11	9700

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000178	124610	0	42	124652	0.000168

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.71	268	425	0.631	0.0000254	4448
Missense in Polyphen		65	162.81	0.39923		1811
Synonymous	0.646	165	176	0.938	0.0000107	1354
Loss of Function	5.04	2	33.4	0.0598	0.00000184	350

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000535	0.000517
Ashkenazi Jewish	0.0000998	0.0000993
East Asian	0.00	0.00
Finnish	0.000753	0.000743
European (Non-Finnish)	0.000134	0.000133
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000336	0.000330

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344). {ECO:0000250|UniProtKB:Q9JI71, ECO:0000269|PubMed:11134954, ECO:0000269|PubMed:17728344, ECO:0000269|PubMed:20616313}.
• Disease: DISEASE: Adams-Oliver syndrome 6 (AOS6) [MIM:616589]: A form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins. {ECO:0000269|PubMed:26299364}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Breast cancer - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);NOTCH-Ncore;Neural Crest Differentiation;Notch Signaling Pathway;NOTCH1 regulation of human endothelial cell calcification;Canonical and Non-canonical Notch signaling;VEGFA-VEGFR2 Signaling Pathway;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Disease;Signal Transduction;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch;Signaling by NOTCH1;Signaling by NOTCH2;NOTCH3 Activation and Transmission of Signal to the Nucleus;Signaling by NOTCH3;Signaling by NOTCH4;Signaling by NOTCH;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;NOTCH2 Activation and Transmission of Signal to the Nucleus;Notch signaling pathway;Constitutive Signaling by NOTCH1 HD Domain Mutants;Signaling by NOTCH1 HD Domain Mutants in Cancer;GPCR signaling-G alpha i;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Diseases of signal transduction;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.206

Intolerance Scores

• loftool: 0.0295
• rvis_EVS: -1.35
• rvis_percentile_EVS: 4.56

Haploinsufficiency Scores

• pHI: 0.967
• hipred: Y
• hipred_score: 0.853
• ghis: 0.651

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.825

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dll4
• Phenotype: hematopoietic system 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); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype; immune system phenotype; vision/eye phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype

Zebrafish Information Network

• Gene name: dll4
• Affected structure: lymphangioblast
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;angiogenesis;branching involved in blood vessel morphogenesis;blood vessel remodeling;aortic valve morphogenesis;cardiac ventricle morphogenesis;cardiac atrium morphogenesis;ventricular trabecula myocardium morphogenesis;pericardium morphogenesis;signal transduction;Notch signaling pathway;visual perception;blood circulation;negative regulation of cell population proliferation;negative regulation of endothelial cell migration;positive regulation of gene expression;negative regulation of gene expression;T cell differentiation;dorsal aorta morphogenesis;cellular response to vascular endothelial growth factor stimulus;cellular response to fibroblast growth factor stimulus;negative regulation of Notch signaling pathway;positive regulation of Notch signaling pathway;ventral spinal cord interneuron fate commitment;regulation of neural retina development;Notch signaling involved in heart development;negative regulation of cell migration involved in sprouting angiogenesis;negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis;positive regulation of neural precursor cell proliferation
• Cellular component: plasma membrane;integral component of membrane
• Molecular function: Notch binding;calcium ion binding;protein binding