DLL1

delta like canonical Notch ligand 1

Basic information

Region (hg38): 6:170282205-170306565

Links

ENSG00000198719 ∙ NCBI:28514 ∙ OMIM:606582 ∙ HGNC:2908 ∙ Uniprot:O00548 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Limited), mode of inheritance: AD
• neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (Moderate), mode of inheritance: AD
• autosomal dominant non-syndromic intellectual disability (Supportive), mode of inheritance: AD
• neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (Strong), mode of inheritance: AD
• neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holoprosencephaly; Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Endocrine; Musculoskeletal; Neurologic	21196490; 31353024
Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DLL1 gene.

• not provided (329 variants)
• Inborn genetic diseases (47 variants)
• Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (46 variants)
• DLL1-related condition (7 variants)
• See cases (3 variants)
• not specified (2 variants)
• Alobar holoprosencephaly (1 variants)
• Holoprosencephaly sequence (1 variants)
• Neurodevelopmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLL1 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			1	87	13	101
missense		1	151	13	7	172
nonsense	7		3			10
start loss						0
frameshift	11	11	1			23
inframe indel				2		2
splice donor/acceptor (+/-2bp)	2	1	1			4
splice region	1		6	8	1	16
non coding			2	25	20	47
Total	20	13	159	127	40

Variants in DLL1

This is a list of pathogenic ClinVar variants found in the DLL1 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-170282680-G-A			Benign (Jun 19, 2019)
6-170282690-G-A			Likely benign (Mar 06, 2021)
6-170282835-T-G			Benign (Apr 12, 2019)
6-170282881-TG-T			Benign/Likely benign (Jan 25, 2024)
6-170282886-G-A			Likely benign (Jul 26, 2022)
6-170282887-G-A			Likely benign (Jun 28, 2023)
6-170282921-A-G			Benign (Dec 22, 2018)
6-170282932-C-G			Benign (Dec 22, 2018)
6-170282968-C-T			Likely benign (Mar 04, 2022)
6-170282969-G-A			Benign (Jan 21, 2024)
6-170283002-C-T			Uncertain significance (Feb 17, 2022)
6-170283003-G-A			Likely benign (Oct 01, 2022)
6-170283004-C-T		Inborn genetic diseases	Uncertain significance (Jan 24, 2024)
6-170283006-C-G		Inborn genetic diseases	Uncertain significance (Dec 10, 2023)
6-170283011-C-T			Uncertain significance (Jul 26, 2023)
6-170283020-C-A		Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures	Uncertain significance (Apr 28, 2023)
6-170283021-G-A			Benign (Apr 01, 2024)
6-170283023-A-G		Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures	Uncertain significance (Jul 18, 2023)
6-170283029-C-A		DLL1-related disorder	Uncertain significance (Oct 05, 2022)
6-170283029-C-T		DLL1-related disorder	Likely benign (May 04, 2023)
6-170283030-G-A			Likely benign (Mar 01, 2024)
6-170283037-G-A		Alobar holoprosencephaly	Uncertain significance (Feb 24, 2023)
6-170283038-A-G			Uncertain significance (Sep 01, 2022)
6-170283072-C-G			Likely benign (Aug 10, 2023)
6-170283073-G-A			Likely benign (Nov 01, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLL1	protein_coding	protein_coding	ENST00000366756	11	8268

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000136	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.82	335	442	0.757	0.0000296	4677
Missense in Polyphen		70	142.21	0.49222		1591
Synonymous	-2.49	239	195	1.23	0.0000150	1397
Loss of Function	5.20	0	31.5	0.00	0.00000156	367

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite- derived muscle via MYOD1 regulation but in cranial mesoderm- derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity). {ECO:0000250|UniProtKB:P97677, ECO:0000250|UniProtKB:Q61483, ECO:0000269|PubMed:11006133, ECO:0000269|PubMed:11581320}.
• 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-Core;Neural Crest Differentiation;Notch Signaling Pathway;Gene regulatory network modelling somitogenesis;Mesodermal Commitment Pathway;NOTCH1 regulation of human endothelial cell calcification;Canonical and Non-canonical Notch signaling;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Disease;Signal Transduction;proteolysis and signaling pathway of notch;segmentation clock;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;Presenilin action in Notch and Wnt signaling;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.599

Intolerance Scores

• loftool: 0.00358
• rvis_EVS: -1.1
• rvis_percentile_EVS: 6.89

Haploinsufficiency Scores

• pHI: 0.746
• hipred: Y
• hipred_score: 0.853
• ghis: 0.555

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.985

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dll1
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; embryo phenotype; renal/urinary system phenotype; skeleton phenotype; immune system phenotype; digestive/alimentary 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); hearing/vestibular/ear phenotype; limbs/digits/tail 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); hematopoietic system 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); normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: dld
• Affected structure: hematopoietic stem cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: cell fate determination;somitogenesis;somite specification;heart looping;marginal zone B cell differentiation;type B pancreatic cell development;Notch signaling pathway;determination of left/right symmetry;compartment pattern specification;regulation of blood pressure;positive regulation of cell population proliferation;negative regulation of cell population proliferation;proximal/distal pattern formation;astrocyte development;regulation of somitogenesis;spinal cord development;cerebellar molecular layer formation;cerebellar Purkinje cell layer structural organization;hemopoiesis;cell differentiation;regulation of cell adhesion;negative regulation of epithelial cell differentiation;negative regulation of interleukin-10 production;negative regulation of glial cell apoptotic process;organ growth;regulation of growth;negative regulation of cell differentiation;negative regulation of epidermal cell differentiation;negative regulation of inner ear auditory receptor cell differentiation;negative regulation of myeloid cell differentiation;negative regulation of myoblast differentiation;negative regulation of neuron differentiation;positive regulation of Notch signaling pathway;positive regulation of endocytosis;positive regulation of transcription by RNA polymerase II;lateral inhibition;skeletal muscle tissue growth;regulation of skeletal muscle tissue growth;positive regulation of skeletal muscle tissue growth;neuron fate specification;inner ear development;regulation of neurogenesis;regulation of cell division;retina development in camera-type eye;retina morphogenesis in camera-type eye;Notch signaling pathway involved in arterial endothelial cell fate commitment;left/right axis specification;nephron development;proximal tubule development;loop of Henle development;clathrin-dependent endocytosis;energy homeostasis;endothelial tip cell fate specification;neuronal stem cell population maintenance;skin epidermis development;regulation of vascular endothelial growth factor signaling pathway;positive regulation of sprouting angiogenesis;negative regulation of cardiac muscle cell differentiation
• Cellular component: extracellular region;plasma membrane;integral component of plasma membrane;adherens junction;apical plasma membrane;cytoplasmic vesicle;membrane raft
• Molecular function: Notch binding;calcium ion binding;protein binding;Tat protein binding;scaffold protein binding