ZNF346

Chr 5

zinc finger protein 346

Also known as: JAZ, Zfp346

NCBI Gene: 23567 ENSG00000113761 UniProt: Q9UL40 OMIM: 605308

The protein is a nucleolar zinc finger protein that binds double-stranded RNA and RNA/DNA hybrids and protects neurons by inhibiting cell cycle re-entry through stimulation of p21 gene expression. Mutations in ZNF346 cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive microcephaly. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a nucleolar, zinc finger protein that preferentially binds to double-stranded (ds) RNA or RNA/DNA hybrids, rather than DNA alone. Mutational studies indicate that the zinc finger domains are not only essential for dsRNA binding, but are also required for its nucleolar localization. The encoded protein may be involved in cell growth and survival. It plays a role in protecting neurons by inhibiting cell cycle re-entry via stimulation of p21 gene expression. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.66

Clinical Summary— ZNF346

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.116

Z-score 2.44

OE 0.29 (0.14–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.17Z-score

OE missense 0.73 (0.63–0.86)

113 obs / 154.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.14–0.66)

0≤0.351.4

Missense OE?0.73 (0.63–0.86)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 4 / 13.8Missense obs/exp: 113 / 154.0Syn Z: 1.16

This gene — mechanism propensity

0.6260th %ile

GOF

0.5758th %ile

LOF

0.4430th %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.