ZBTB7A

Chr 19AD

zinc finger and BTB domain containing 7A

Also known as: FBI-1, FBI1, LRF, MNDLFH, TIP21, ZBTB7, ZNF857A, pokemon

NCBI Gene: 51341 ENSG00000178951 UniProt: O95365 OMIM: 605878

The ZBTB7A protein is a transcription factor that represses genes involved in cell proliferation, differentiation, and the switch from fetal to adult hemoglobin expression during red blood cell development. Mutations cause autosomal dominant macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin. This gene is highly constrained against loss-of-function variants, with primary involvement of the nervous system, immune system, and hematopoietic system.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.331 OMIM phenotype

Clinical Summary— ZBTB7A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.33LOEUF

pLI 0.959

Z-score 3.27

OE 0.07 (0.02–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.04Z-score

OE missense 0.43 (0.38–0.49)

175 obs / 403.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.07 (0.02–0.33)

0≤0.351.4

Missense OE0.43 (0.38–0.49)

0≤0.61.4

Synonymous OE0.83

0≤1.21.6

LoF obs/exp: 1 / 14.4Missense obs/exp: 175 / 403.5Syn Z: 1.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateZBTB7A-related developmental disorder with macrocephaly, obstructive sleep apnea, and persistent fetal hemoglobinLOFAD

0.2798th %ile

GOF

0.2994th %ile

LOF

0.83top 5%

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

LOFprediction above median · LOEUF 0.33

DN1 literature citation

Literature Evidence

DNWe identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn2+ ion at thePMID:31645653

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