NFIB

Chr 9

nuclear factor I B

Also known as: CTF, HMGIC/NFIB, MACID, NF-I/B, NF1-B, NFI-B, NFI-RED, NFIB2

NCBI Gene: 4781 ENSG00000147862 UniProt: O00712

NFIB encodes a transcriptional activator essential for proper brain development that recognizes specific DNA sequences in viral and cellular promoters. Mutations cause autosomal dominant macrocephaly with impaired intellectual development. This gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.225), indicating that such variants are likely pathogenic.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Enables DNA-binding transcription activator activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and transcription regulator inhibitor activity. Involved in brain development and regulation of DNA-templated transcription. Located in fibrillar center and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.23

Clinical Summary— NFIB

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

35 unique Pathogenic / Likely Pathogenic· 114 VUS of 199 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NFIB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.999

Z-score 4.55

OE 0.07 (0.03–0.23)

Highly constrained

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

Missense Constraint?

2.47Z-score

OE missense 0.57 (0.50–0.65)

151 obs / 264.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.23)

0≤0.351.4

Missense OE?0.57 (0.50–0.65)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 2 / 27.9Missense obs/exp: 151 / 264.2Syn Z: -1.38

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNFIB-related macrocephaly, acquired, with impaired intellectual developmentLOFAD

This gene — mechanism propensity

0.4190th %ile

GOF

0.3391th %ile

LOF

0.82top 5%

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

LOFprediction above median · 1 literature citation · 77% of P/LP variants are LoF · LOEUF 0.23 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFNFIB haploinsufficiency is associated with intellectual disability and macrocephaly.1

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

References

1.PMID 30388402 ↗

ClinVar Variant Classifications

199 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic22

VUS114

Likely Benign23

Benign3

Conflicting3

Pathogenic

Likely Pathogenic

114

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	1	0	0	13
Likely Pathogenic	15	7	0	0	22
VUS	7	96	11	0	114
Likely Benign	0	11	2	10	23
Benign	0	3	0	0	3
Conflicting	—				3
Total	34	118	13	10	178

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

View in ClinVar →

132 pathogenic / likely-pathogenic (of 145) ClinVar copy-number / structural variants overlap NFIB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →