DLL3

delta like canonical Notch ligand 3

Basic information

Region (hg38): 19:39498895-39508481

Links

ENSG00000090932 ∙ NCBI:10683 ∙ OMIM:602768 ∙ HGNC:2909 ∙ Uniprot:Q9NYJ7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spondylocostal dysostosis 1, autosomal recessive (Definitive), mode of inheritance: AR
• autosomal recessive spondylocostal dysostosis (Supportive), mode of inheritance: AR
• spondylocostal dysostosis 1, autosomal recessive (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spondylocostal dysostosis 1, autosomal recessive	AR	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	Musculoskeletal	2805381; 10742114; 12746394; 15200511

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DLL3 gene.

• not provided (22 variants)
• Spondylocostal dysostosis 1, autosomal recessive (4 variants)
• Hemivertebrae;Rib fusion (1 variants)
• Leukodystrophy and acquired microcephaly with or without dystonia; (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLL3 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			3	224	6	233
missense		3	137	9	4	153
nonsense	11	3				14
start loss						0
frameshift	12	4	2			18
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	3				4
splice region			4	22		26
non coding			6	57	20	83
Total	24	13	149	290	30

Highest pathogenic variant AF is 0.0000658

Variants in DLL3

This is a list of pathogenic ClinVar variants found in the DLL3 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-39498956-A-AC		Syndactyly • Spondylocostal dysostosis	Uncertain significance (Jun 14, 2016)
19-39498978-G-T			Uncertain significance (Feb 05, 2022)
19-39498983-C-G			Likely benign (Jan 29, 2024)
19-39498989-G-A			Likely benign (Jan 22, 2024)
19-39498998-G-C			Likely benign (Nov 24, 2022)
19-39498998-G-T			Likely benign (Dec 19, 2023)
19-39499005-T-C		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
19-39499036-TC-T			Uncertain significance (Sep 16, 2018)
19-39499037-C-T		not specified • Syndactyly • Spondylocostal dysostosis 1, autosomal recessive	Benign/Likely benign (Jan 31, 2024)
19-39499040-C-T			Likely benign (Jan 11, 2024)
19-39499184-C-T			Likely benign (Oct 17, 2022)
19-39499185-G-A			Likely benign (Mar 24, 2022)
19-39499187-C-G			Likely benign (Dec 03, 2023)
19-39499188-C-T		DLL3-related disorder	Benign (Jan 28, 2024)
19-39499195-C-A			Likely benign (Feb 09, 2023)
19-39499197-G-A			Likely benign (Oct 06, 2023)
19-39499205-G-C			Uncertain significance (Aug 24, 2021)
19-39499218-G-A			Likely benign (Nov 17, 2023)
19-39499222-A-T		Syndactyly • Spondylocostal dysostosis 1, autosomal recessive • Inborn genetic diseases	Uncertain significance (Jan 04, 2024)
19-39499224-C-T			Likely benign (Jan 25, 2024)
19-39499230-T-C			Likely benign (Jul 17, 2023)
19-39499236-G-T			Likely benign (Jan 11, 2024)
19-39499239-G-A			Likely benign (Aug 24, 2023)
19-39499241-G-A		Inborn genetic diseases	Uncertain significance (Apr 04, 2023)
19-39499254-G-C			Likely benign (Aug 24, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLL3	protein_coding	protein_coding	ENST00000205143	8	9587

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000536	0.972	125713	0	35	125748	0.000139

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.329	318	335	0.949	0.0000181	3786
Missense in Polyphen		133	141.35	0.94093		1643
Synonymous	-1.70	176	150	1.18	0.00000867	1357
Loss of Function	1.98	10	19.4	0.515	0.00000103	225

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000210	0.000210
Ashkenazi Jewish	0.000893	0.000893
East Asian	0.000282	0.000272
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000970	0.0000967
Middle Eastern	0.000282	0.000272
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inhibits primary neurogenesis. May be required to divert neurons along a specific differentiation pathway. Plays a role in the formation of somite boundaries during segmentation of the paraxial mesoderm (By similarity). {ECO:0000250}.
• Disease: DISEASE: Spondylocostal dysostosis 1, autosomal recessive (SCDO1) [MIM:277300]: A condition of variable severity associated with vertebral and rib segmentation defects. The main skeletal malformations include fusion of vertebrae, hemivertebrae, fusion of certain ribs, and other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of the malformation and leads to a dwarf- like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections resulting in life-threatening complications in the first year of life. {ECO:0000269|PubMed:10742114}. 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;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Notch;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Notch signaling pathway;GPCR signaling-G alpha i (Consensus)

Recessive Scores

• pRec: 0.140

Haploinsufficiency Scores

• pHI: 0.511
• hipred: N
• hipred_score: 0.367
• ghis: 0.548

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.764

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dll3
• Phenotype: craniofacial phenotype; muscle phenotype; growth/size/body region phenotype; embryo phenotype; skeleton phenotype; limbs/digits/tail 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); reproductive 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: dlb
• Affected structure: posterior lateral line ganglion
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: skeletal system development;somitogenesis;Notch signaling pathway;compartment pattern specification;paraxial mesoderm development;negative regulation of neurogenesis
• Cellular component: integral component of membrane
• Molecular function: Notch binding;calcium ion binding