DLL4

Chr 15AD

delta like canonical Notch ligand 4

Also known as: AOS6, delta4, hdelta2

NCBI Gene: 54567 ENSG00000128917 UniProt: Q9NR61 OMIM: 605185

This gene is a homolog of the Drosophila delta gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Adams-Oliver syndrome 6MIM #616589

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Adams-Oliver syndrome 6; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

132

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.04

OE 0.06 (0.02–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.71Z-score

OE missense 0.63 (0.57–0.70)

268 obs / 425.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.19)

0≤0.351.4

Missense OE?0.63 (0.57–0.70)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 2 / 33.4Missense obs/exp: 268 / 425.0Syn Z: 0.65

Background carrier burden — how many people carry a rare variant somewhere in DLL4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 80

668 rare PASS variants

Rare truncating (LoF)

1 in 13,000

17 rare PASS variants

Rare synonymous (reference)

1 in 120

365 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DLL4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 20,000
South Asian	~43k	1 in 78	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 78	none seen
European (Finnish)	~27k	1 in 190	1 in 5,100
Admixed American	~22k	1 in 86	none seen
African / African American	~21k	1 in 90	≈ 1 in 6,900
East Asian	~20k	1 in 85	none seen
Ashkenazi Jewish	~13k	1 in 570	none seen
Middle Eastern	~2,884	1 in 86	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓