NFIA

protein-coding

nuclear factor I A, the group of Nuclear factor I family

Gene summary

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]

MANE transcript

NM_001134673.4

Inheritance

ClinVar variants

P:78U:152B:79

Top phenotype

Brain malformations with or without urinary tract defects

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr1:60,865,259-61,462,788

External References & Databases

Ensembl (ENSG00000162599)

Transcript & Mutation Effects

hg38 • Region Span ~597.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

chromosome 1p32-p31 deletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013396

Submitter: Ambry Genetics

brain malformations with or without urinary tract defectsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100478

Submitter: G2P

brain malformations with or without urinary tract defectsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100478

Submitter: PanelApp Australia

chromosome 1p32-p31 deletion syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013396

Submitter: Illumina

brain malformations with or without urinary tract defectsDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100478

Submitter: ClinGen

NFIA was first reported in relation to autosomal dominant brain malformations with or without urinary tract defects in 2007 (Lu et al., PMID: 17530927). Most individuals present with some combination of agenesis of the corpus callosum, ventriculomegaly, developmental delay, intellectual disability, and/or urinary tract defects. Seven variants (nonsense, frameshift, large deletion etc) that have been reported in seven probands in six publications (PMIDs: 22542183, 24462883, 27081522, 28941020, 32926563, 35080095) are included in this curation. The variants reported in this curation arose de novo as did most observed variants throughout the literature. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by demonstrated biochemical function, expression in relevant tissues, and a knockout mouse model (PMIDs: 10718198, 17530927, 26512640, 29247144). In summary, NFIA is definitively associated with autosomal dominant brain malformations with or without urinary tract defects. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 10/11/2022 (SOP Version 9).

brain malformations with or without urinary tract defectsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100478

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Brain malformations with or without urinary tract defectsAD

Manifestation: Neurologic; Renal

Intervention: Renal

Rationale: The condition can include renal anomalies such as hydronephrosis and vesicoureteral reflux and awareness may allow early management, which may help prevent or manage renal sequelae

Refs: 17530927; 24462883; 27081522

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFIA variants in ClinVar

12 Conditions Cataloged

not providedTotal: 286

Inborn genetic diseasesTotal: 51

Brain malformations with or without urinary tract defectsTotal: 44

NFIA-Related DisorderTotal: 34

not specifiedTotal: 28

Chromosome 1p32-p31 deletion syndromeTotal: 14

Paediatric disordersTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134673.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				69 clinvar		69
missense	2 clinvar	10 clinvar	144 clinvar	10 clinvar		166
nonsense	12 clinvar	11 clinvar	2 clinvar			25
start loss	1 clinvar	1 clinvar	1 clinvar			3
frameshift	13 clinvar	22 clinvar	1 clinvar			36
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	4 clinvar			10
Total	31	47	152	79	0	309

Highest pathogenic variant AF is 0.00004671333

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134673.4	RefSeq	NP_001128145.1	11	MANE Select
ENST00000403491.8	Ensembl	ENSP00000384523.3	11	MANE Select
NM_001145511.2	RefSeq	NP_001138983.1	11	Standard
NM_001145512.2	RefSeq	NP_001138984.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Gene expression (Transcription)
RNA Polymerase III Transcription Termination
FOXA1 transcription factor network

Biological Process

negative regulation of transcription by RNA polymerase II
DNA replication
regulation of transcription, DNA-templated
viral genome replication
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
chromatin binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371189
Coding exons: 12
Length: 597535
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.23	158	321	0.492	0.0000181	3571
Missense (PolyPhen)		44	137.52	0.31996		1539
Synonymous	-0.114	123	121	1.01	0.00000697	1123
Loss of Function	4.85	2	31.2	0.0640	0.00000202	323

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Recognizes and binds the palindromic sequence 5'- TTGGCNNNNNGCCAA-3' present in viral and cellular promoters and in the origin of replication of adenovirus type 2. These proteins are individually capable of activating transcription and replication.;
Disease: DISEASE: Brain malformations with or without urinary tract defects (BRMUTD) [MIM:613735]: A syndrome characterized by corpus callosum hypoplasia or agenesis, hydrocephalus or ventricular enlargement, developmental delay, and urinary tract defects. {ECO:0000269|PubMed:24462883, ECO:0000269|PubMed:27081522}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.361

Intolerance Scores

LoFtool: 0.0782
RVIS EVS: -0.54
RVIS percentile EVS: 20.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.563

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium