ZFHX3

Chr 16ADAR

zinc finger homeobox 3

Also known as: ATBF1, ATBT, ATFB8, C16orf47, EIG20, SCA4, ZFH-3, ZNF927

NCBI Gene: 463 ENSG00000140836 UniProt: Q15911 OMIM: 104155

This gene encodes a transcription factor that regulates myogenic and neuronal differentiation and controls circadian locomotor rhythms in the brain. Mutations cause spinocerebellar ataxia 4, idiopathic generalized epilepsy, and susceptibility to atrial fibrillation with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.136), indicating intolerance to protein-truncating mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.144 OMIM phenotypes

Clinical Summary— ZFHX3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

45 unique Pathogenic / Likely Pathogenic· 636 VUS of 969 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ZFHX3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 9.52

OE 0.08 (0.05–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

-1.23Z-score

OE missense 1.08 (1.04–1.11)

2279 obs / 2119.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.08 (0.05–0.14)

0≤0.351.4

Missense OE?1.08 (1.04–1.11)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 10 / 124.8Missense obs/exp: 2279 / 2119.1Syn Z: -6.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateZFHX3-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.2897th %ile

GOF

0.2597th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 89% of P/LP variants are LoF · LOEUF 0.14

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

969 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic24

VUS636

Likely Benign141

Benign90

Conflicting16

Pathogenic

Likely Pathogenic

636

VUS

141

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	2	2	0	21
Likely Pathogenic	23	1	0	0	24
VUS	31	596	6	3	636
Likely Benign	0	39	13	89	141
Benign	0	42	16	32	90
Conflicting	—				16
Total	71	680	37	124	928

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap ZFHX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →