ZNF597

Chr 16

zinc finger protein 597

Also known as: HIT-4

NCBI Gene: 146434 ENSG00000167981 UniProt: Q96LX8 OMIM: 614685

This gene encodes a zinc finger protein that may be involved in transcriptional regulation and is maternally expressed due to genomic imprinting. Mutations cause neurodevelopmental disorders with intellectual disability and developmental delay, following a maternal inheritance pattern due to the gene's imprinted status. The gene shows low constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein with multiple zinc finger domains. Loss of the related gene in rodents results in defects in neural development and embryonic lethality in mutant homozygotes. This gene is adjacent to a differentially methylated region (DMR) and is imprinted and maternally expressed. [provided by RefSeq, Nov 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.99

Clinical Summary— ZNF597

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.07) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

53 VUS of 62 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?

0.99LOEUF

pLI 0.066

Z-score 1.60

OE 0.38 (0.17–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.54Z-score

OE missense 1.10 (0.99–1.22)

256 obs / 232.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.38 (0.17–0.99)

0≤0.351.4

Missense OE?1.10 (0.99–1.22)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 7.8Missense obs/exp: 256 / 232.8Syn Z: -0.77

This gene — mechanism propensity

0.7034th %ile

GOF

0.6637th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

62 submitted variants in ClinVar

ClinVar

Classification Summary

VUS53

Likely Benign4

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	53	0	53
Likely Benign	4	0	4
Benign	0	2	2
Total	57	2	59

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 50) ClinVar copy-number / structural variants overlap ZNF597 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →