Human Gene Module / Chromosome 12 / NAV3

NAV3neuron navigator 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
43 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
12q21.2
Associated Disorders
-
Relevance to Autism

A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified NAV3 as a gene reaching exome-wide significance (P < 2.5E-06); association of NAV3 with ASD risk was primarily driven by rare inherited loss-of-function variants.

Molecular Function

This gene belongs to the neuron navigator family and is expressed predominantly in the nervous system. The encoded protein contains coiled-coil domains and a conserved AAA domain characteristic for ATPases associated with a variety of cellular activities. This gene is similar to unc-53, a Caenorhabditis elegans gene involved in axon guidance.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NAV3 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary - Zhou X et al. (2022) Yes -
3 Support - Yuan B et al. (2023) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
5 Support - Thomas V Fernandez et al. (2023) No -
6 Support - Amama Ghaffar et al. (2024) No ADHD, stereotypy
Rare Variants   (43)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.163C>T p.Gln55Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.187G>T p.Glu63Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.604C>T p.Arg202Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.2080C>T p.Gln694Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.2206C>T p.Arg736Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.3454C>T p.Arg1152Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.5638C>T p.Gln1880Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.5899C>T p.Arg1967Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.6330C>A p.Cys2110Ter stop_gained Familial - - 35982159 Zhou X et al. (2022)
c.148T>G p.Ser50Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.466G>A p.Val156Ile missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.163C>T p.Gln55Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.163C>T p.Gln55Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.4630+2T>C - splice_site_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.5125-1G>A - splice_site_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.2547T>G p.Tyr849Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.5782C>T p.Arg1928Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.5791-2A>T - splice_site_variant Unknown Not maternal - 35982159 Zhou X et al. (2022)
c.232del p.Glu78LysfsTer14 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1199dup p.Gln401AlafsTer8 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.2246del p.Pro749ArgfsTer53 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.6204dup p.Leu2069ThrfsTer3 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3429del p.Lys1143AsnfsTer36 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.3766del p.Ala1256GlnfsTer14 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1611A>G p.Val537= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1646_1647del p.Lys549ArgfsTer3 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.5043C>G p.Ser1681Arg missense_variant De novo - Simplex 38977784 Amama Ghaffar et al. (2024)
c.3060del p.Ala1021LeufsTer9 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.5414del p.Ser1805ThrfsTer8 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.4057dup p.Ser1353PhefsTer16 frameshift_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.4138del p.Leu1380SerfsTer10 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.5907A>T p.Arg1969Ser missense_variant De novo - Simplex 37788244 Thomas V Fernandez et al. (2023)
c.996G>A p.Trp332Ter stop_gained Familial Both parents Simplex 38977784 Amama Ghaffar et al. (2024)
c.6810G>A p.Trp2270Ter stop_gained Familial Maternal Multiplex 38977784 Amama Ghaffar et al. (2024)
c.1940_1941dup p.Ser648HisfsTer37 frameshift_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.929_944del p.Gln310LeufsTer23 frameshift_variant Unknown Not maternal - 35982159 Zhou X et al. (2022)
c.3659_3660dup p.Ser1221ProfsTer50 frameshift_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.3621dup p.Asp1208ArgfsTer58 frameshift_variant De novo - Simplex 38977784 Amama Ghaffar et al. (2024)
c.4377_4380del p.Pro1460TrpfsTer21 frameshift_variant Familial - Multiplex 35982159 Zhou X et al. (2022)
c.3977G>A p.Ser1326Asn missense_variant Familial Both parents Multiplex 38977784 Amama Ghaffar et al. (2024)
c.6847C>T p.Arg2261Cys missense_variant Familial Both parents Multiplex 38977784 Amama Ghaffar et al. (2024)
c.2173G>C p.Val725Leu missense_variant De novo - Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
c.4848_4849del p.Thr1617TyrfsTer9 frameshift_variant Familial Both parents Simplex 38977784 Amama Ghaffar et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

10/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.68000000000001

Ranking 39/25841 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 0.99999939886181

Ranking 275/18225 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
Sanders TADA Score

Score 0.94956244839398

Ranking 18141/18665 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
Zhang D Score

Score 0.52443835377733

Ranking 359/20870 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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