DNASE1

Chr 16AD

deoxyribonuclease 1

Also known as: DNL1, DRNI

NCBI Gene: 1773 ENSG00000213918 UniProt: P24855 OMIM: 125505

The protein is a serum endonuclease that cleaves DNA and degrades neutrophil extracellular traps to prevent clot formation during inflammation. Mutations cause systemic lupus erythematosus, an autoimmune disease with autosomal codominant inheritance. The gene shows extremely low constraint against loss-of-function variants, suggesting tolerance to reduced protein levels.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the DNase family. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner. At least six autosomal codominant alleles have been characterized, DNASE1*1 through DNASE1*6, and the sequence of DNASE1*2 represented in this record. Mutations in this gene have been associated with systemic lupus erythematosus (SLE), an autoimmune disease. A recombinant form of this protein is used to treat the one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 1.951 OMIM phenotype

Clinical Summary— DNASE1

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Gene-Disease Validity (ClinGen)

systemic lupus erythematosus · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 174 VUS of 272 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -2.34

OE 1.65 (1.17–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.55Z-score

OE missense 1.55 (1.40–1.72)

264 obs / 170.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.65 (1.17–1.95)

0≤0.351.4

Missense OE?1.55 (1.40–1.72)

0≤0.61.4

Synonymous OE?1.51

0≤1.21.6

LoF obs/exp: 25 / 15.2Missense obs/exp: 264 / 170.5Syn Z: -3.56

This gene — mechanism propensity

0.6357th %ile

GOF

0.5759th %ile

LOF

0.2679th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

272 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS174

Likely Benign54

Benign21

Conflicting7

Pathogenic

Likely Pathogenic

174

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	0	0	0	1
VUS	16	151	6	1	174
Likely Benign	0	7	11	36	54
Benign	1	9	8	3	21
Conflicting	—				7
Total	19	167	25	40	258

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap DNASE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →