NFIA

Chr 1AD

nuclear factor I A

Also known as: BRMUTD, C1DELp32p31, CTF, DEL1P32P31, NF-I/A, NF1-A, NFI-A, NFI-L

NCBI Gene: 4774 ENSG00000162599 UniProt: Q12857 OMIM: 600727

This gene encodes a transcription factor that recognizes and binds specific palindromic DNA sequences in viral and cellular promoters to activate transcription and replication. Mutations cause brain malformations with or without urinary tract defects with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.20), indicating that haploinsufficiency is likely not tolerated in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the NF1 (nuclear factor 1) family of transcription factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Brain malformations with or without urinary tract defectsMIM #613735

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · brain malformations with or without urinary tract defects · AD · ClinGen 2022

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

0.20

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — NFIA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 4.85

OE 0.06 (0.03–0.20)

Highly constrained

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

Missense Constraint?

3.23Z-score

OE missense 0.49 (0.43–0.56)

158 obs / 320.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.20)

0≤0.351.4

Missense OE?0.49 (0.43–0.56)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 2 / 31.2Missense obs/exp: 158 / 320.9Syn Z: -0.11

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

586 rare PASS variants

Rare truncating (LoF)

1 in 1,400

69 rare PASS variants

Rare synonymous (reference)

1 in 160

317 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NFIA. 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 230	1 in 1,800
South Asian	~43k	1 in 110	1 in 990
Remaining (unassigned)	~30k	1 in 180	1 in 300
European (Finnish)	~27k	1 in 230	1 in 4,500
Admixed American	~22k	1 in 200	1 in 780
African / African American	~21k	1 in 160	1 in 1,000
East Asian	~20k	1 in 280	1 in 1,200
Ashkenazi Jewish	~13k	1 in 460	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 310	≈ 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.

Exome coverage (gnomAD): 8 of 11 coding exons well covered in gnomAD exomes; exons 5, 10, 11 marginal. Genomes: 9 of 11 (exons 1, 10 below).? see exons ↓