Human Gene Module / Chromosome 1 / NFIA

NFIAnuclear factor I/A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 19
Rare Variants / Common Variants
29 / 0
Aliases
NFIA, RP5-902P15.1,  CTF,  NF-I/A,  NF1-A,  NFI-A,  NFI-L
Associated Syndromes
-
Chromosome Band
1p31.3
Associated Disorders
BPD, ID
Relevance to Autism

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02). A rare deletion in the NFIA gene has been identified with intellectual disability and bipolar disorder (PMID 22031302).

Molecular Function

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. This protein 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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NFIA (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders Mikhail FM , et al. (2011) No BPD
2 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
3 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
7 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
8 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
9 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
10 Recent Recommendation Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes Hickey SL , et al. (2019) No -
11 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
12 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
13 Support - Alonso-Gonzalez A et al. (2021) Yes -
14 Support - Li D et al. (2022) Yes -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Sanchis-Juan A et al. (2023) Yes -
17 Support - Gianluca Dini et al. (2023) No ADHD
18 Support - Peyton Paschell et al. (2024) Yes ADHD, BPD, MDD
19 Support - Isabelle Schrauwen et al. (2024) No -
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss - - - 22031302 Mikhail FM , et al. (2011)
insT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - inversion De novo - Simplex 38755281 Isabelle Schrauwen et al. (2024)
c.946+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.946+1G>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.66C>A p.Cys22Ter stop_gained Unknown - - 27824329 Wang T , et al. (2016)
c.625+19661del - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.1A>G p.Met1? initiator_codon_variant Unknown - - 34968013 Li D et al. (2022)
c.998C>G p.Pro333Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1301G>A p.Arg434His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.261T>G p.Tyr87Ter stop_gained De novo - - 37915986 Gianluca Dini et al. (2023)
c.385C>T p.Arg129Ter stop_gained Familial Maternal - 33004838 Wang T et al. (2020)
c.247C>T p.Arg83Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.344G>A p.Arg115Gln missense_variant De novo - - 37915986 Gianluca Dini et al. (2023)
c.839del p.Pro280GlnfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1052-1G>C p.? splice_site_variant De novo - Unknown 31130284 Monies D , et al. (2019)
c.523G>C p.Asp175His missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.950C>T p.Thr317Met missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1547C>A p.Thr516Lys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1049G>A p.Ser350Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1594G>A p.Val532Ile missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1186C>T p.Arg396Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.607_609dup p.Asn203dup inframe_insertion De novo - Simplex 35982159 Zhou X et al. (2022)
c.397C>T p.Arg133Ter stop_gained Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.161A>C p.Gln54Pro missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.887_888del p.Gly296AlafsTer16 frameshift_variant De novo - - 37915986 Gianluca Dini et al. (2023)
c.362G>C p.Arg121Pro missense_variant Familial Maternal Multiplex 38188845 Peyton Paschell et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2020
3
icon
3

Decreased from 3 to 3

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
4/1/2019
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.2019]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental...2011] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
5
icon
4

Decreased from 5 to 4

Description

A de novo nonsense variant in the NFIA gene was identified in an ASD proband from the Simons Simplex Collection in PMID 22542183. PMID 25961944 identified a de novo missense variant in another ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.02).

4/1/2015
5
icon
5

Decreased from 5 to 5

Description

A de novo, missense likely gene disrupting" variant was reported in Iossifov et al 2012"

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

A de novo, missense likely gene disrupting" variant was reported in Iossifov et al 2012"

4/1/2014
No data
icon
5

Increased from No data to 5

Description

A de novo, missense likely gene disrupting" variant was reported in Iossifov et al 2012"

Krishnan Probability Score

Score 0.49719523291981

Ranking 2434/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99955516621287

Ranking 912/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.874

Ranking 172/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.48542395222385

Ranking 418/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 9

Ranking 198/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.11648799868871

Ranking 12995/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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