ZRANB3

Chr 2

zinc finger RANBP2-type containing 3

ENSG00000121988 UniProt: Q5FWF4 OMIM: 615655

ZRANB3 encodes a DNA annealing helicase and endonuclease that maintains genome stability by facilitating restart of stalled replication forks and preventing inappropriate recombination during DNA repair. Mutations cause autosomal recessive intellectual disability with seizures and brain abnormalities. The gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, UniProt

DNA annealing helicase and endonuclease required to maintain genome stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events (PubMed:21078962, PubMed:22704558, PubMed:22705370, PubMed:22759634, PubMed:26884333). Recruited to the sites of stalled DNA replication by polyubiquitinated PCNA and acts as a structure-specific endonuclease that cleaves the replication fork D-loop intermediate, generating an accessible 3'-OH group in the template of the leading strand, which is amenable to extension by DNA polymerase (PubMed:22759634, PubMed:28621305). In addition to endonuclease activity, also catalyzes the fork regression via annealing helicase activity in order to prevent disintegration of the replication fork and the formation of double-strand breaks (PubMed:22704558, PubMed:22705370)

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.95

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.000

Z-score 1.87

OE 0.73 (0.56–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.49Z-score

OE missense 0.94 (0.87–1.01)

502 obs / 533.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.73 (0.56–0.95)

0≤0.351.4

Missense OE?0.94 (0.87–1.01)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 40 / 55.0Missense obs/exp: 502 / 533.8Syn Z: 0.56

Background carrier burden — how many people carry a rare variant somewhere in ZRANB3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 49

1,383 rare PASS variants

Rare truncating (LoF)

1 in 320

298 rare PASS variants

Rare synonymous (reference)

1 in 82

439 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZRANB3. 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 80	1 in 410
South Asian	~43k	1 in 34	1 in 260
Remaining (unassigned)	~30k	1 in 34	1 in 230
European (Finnish)	~27k	1 in 200	1 in 1,700
Admixed American	~22k	1 in 41	1 in 330
African / African American	~21k	1 in 41	1 in 240
East Asian	~20k	1 in 39	1 in 250
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 41	1 in 360

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): 17 of 20 coding exons well covered in gnomAD exomes; exons 3, 7, 16 marginal. Genomes: 19 of 20 (exon 3 below).? see exons ↓