ZNHIT3

Chr 17AR

zinc finger HIT-type containing 3

Also known as: Hit1, PEHO, TRIP3

NCBI Gene: 9326 ENSG00000273611 UniProt: Q15649 OMIM: 604500

The protein enables nuclear thyroid hormone receptor binding and is involved in ribosomal RNA processing and small nucleolar RNA assembly. Mutations cause PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy), a severe early-onset neurodevelopmental disorder with characteristic brain imaging findings, seizures, and visual impairment. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

Predicted to enable nuclear thyroid hormone receptor binding activity. Predicted to be involved in box C/D snoRNP assembly and maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA). Located in cytoplasm and nucleus. Implicated in PEHO syndrome. [provided by Alliance of Genome Resources, Jun 2026]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

PEHO syndromeMIM #260565

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists PEHO syndrome; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.80

LOEUF

—

Mechanism

📖

GeneReview available — ZNHIT3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.80LOEUF

pLI 0.000

Z-score -0.33

OE 1.13 (0.67–1.80)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.60Z-score

OE missense 1.19 (1.01–1.40)

98 obs / 82.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.13 (0.67–1.80)

0≤0.351.4

Missense OE?1.19 (1.01–1.40)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 9 / 8.0Missense obs/exp: 98 / 82.5Syn Z: -0.46

Background carrier burden — how many people carry a rare variant somewhere in ZNHIT3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

268 rare PASS variants

Rare truncating (LoF)

1 in 990

94 rare PASS variants

Rare synonymous (reference)

1 in 440

102 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZNHIT3. 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 340	1 in 1,200
South Asian	~43k	1 in 160	1 in 380
Remaining (unassigned)	~30k	1 in 190	1 in 2,300
European (Finnish)	~27k	1 in 1,800	1 in 3,300
Admixed American	~22k	1 in 330	1 in 980
African / African American	~21k	1 in 160	1 in 520
East Asian	~20k	1 in 110	1 in 820
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,884	1 in 410	≈ 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.