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…

LOFmechanismADLOEUF 0.201 OMIM phenotype

Clinical Summary— NFIA

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Gene-Disease Validity (ClinGen)

brain malformations with or without urinary tract defects · 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

69 unique Pathogenic / Likely Pathogenic· 161 VUS of 440 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNFIA-related macrocephaly with intellectual disabilityLOFAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.3293th %ile

LOF

0.87top 5%

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

LOFprediction above median · 1 literature citation · 80% of P/LP variants are LoF · LOEUF 0.20 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFWe describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion.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 17530927 ↗

ClinVar Variant Classifications

440 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34

Likely Pathogenic35

VUS161

Likely Benign140

Benign41

Conflicting9

Pathogenic

Likely Pathogenic

161

VUS

140

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	4	3	0	34
Likely Pathogenic	28	7	0	0	35
VUS	4	139	18	0	161
Likely Benign	0	8	63	69	140
Benign	0	0	40	1	41
Conflicting	—				9
Total	59	158	124	70	420

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap NFIA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →