Human Gene Module / Chromosome 7 / TNPO3

TNPO3transportin 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
11 / 0
EAGLE Score
6.35
Moderate Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
7q32.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

TNPO3 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were four damaging de novo missense variants (defined as having a REVEL score > 0.5). Whole-exome sequencing on 67 families with ASD and abnormal head circumference from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wu et al., 2020 had previously identified a de novo missense variant in TNPO3 in an ASD proband who also presented with macrocephaly; furthermore, the authors observed an excess of TNPO3 de novo variants in 10,842 previously published cases with neurodevelopmental disorders (NDDs) deposited in denovo-db (P = 5.9E-08, Padj = 0.001, CH model; P = 1.3E-06, Padj = 0.026, denovolyzeR model; Bonferroni correction).

Molecular Function

The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. Mutations in TNPO3 are responsible for autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2; OMIM 608423), an autosomal dominant myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients (Melia et al., 2013; Torella et al., 2013).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TNPO3 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Melià MJ et al. (2013) No -
2 Support - Torella A et al. (2013) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes -
6 Primary - Zhou X et al. (2022) Yes -
7 Support - Wang J et al. (2023) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
9 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.873-2A>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.232C>G p.Leu78Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.250G>T p.Ala84Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1037G>T p.Trp346Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1043G>T p.Arg348Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2015G>C p.Cys672Ser missense_variant De novo - Simplex 31674007 Wu H , et al. (2019)
c.2540C>G p.Pro847Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1673C>T p.Ala558Val missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1840C>T p.Arg614Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2542del p.Tyr848IlefsTer25 frameshift_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2644del p.Tyr882IlefsTer25 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.44814128240432

Ranking 11740/25841 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 0.0013892014781307

Ranking 11550/18225 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 0.19253061812935

Ranking 107/18665 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 0.36335622106318

Ranking 1862/20870 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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