NFIB

Chr 9AD

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 OMIM: 600728

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Macrocephaly, acquired, with impaired intellectual developmentMIM #618286

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic complex neurodevelopmental disorder · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — NFIB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

668 rare PASS variants

Rare truncating (LoF)

1 in 2,900

50 rare PASS variants

Rare synonymous (reference)

1 in 260

315 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NFIB. 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 150	1 in 3,500
South Asian	~43k	1 in 140	≈ 1 in 11,000
Remaining (unassigned)	~30k	1 in 150	≈ 1 in 6,800
European (Finnish)	~27k	1 in 230	≈ 1 in 13,000
Admixed American	~22k	1 in 140	1 in 700
African / African American	~21k	1 in 100	1 in 2,400
East Asian	~20k	1 in 100	1 in 720
Ashkenazi Jewish	~13k	1 in 210	none seen
Middle Eastern	~2,884	1 in 130	≈ 1 in 1,500

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.

Exome coverage (gnomAD): 8 of 11 coding exons well covered in gnomAD exomes; exons 4, 9, 11 marginal. Genomes: all 11.? see exons ↓