Human Gene Module / Chromosome 11 / HNRNPUL2

HNRNPUL2heterogeneous nuclear ribonucleoprotein U like 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
20 / 0
Aliases
HNRNPUL2, HNRPUL2,  SAF-A2
Associated Syndromes
-
Chromosome Band
11q12.3
Associated Disorders
ADHD, EPS
Relevance to Autism

Gillentine et al., 2021 reported six previously unpublished individuals with likely gene-disruptive (LGD) variants in the HNRNPUL2 gene, including three ASD probands from the SPARK cohort with de novo LGD variants; neurodevelopmental abnormalities (developmental delay, intellectual disability, and/or specific learning disability), motor delay, delayed speech and language development or speech articulation difficulties, behavioral abnormalities, and autism spectrum disorder were frequently observed in this cohort. A de novo missense variant in this gene had previously been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases for the SPARK cohort, in Zhou et al., 2022 identified HNRNPUL2 as a gene reaching exome-wide significance (P < 2.5E-06); association of HNRNPUL2 with ASD risk was primarily driven by de novo variants.

Molecular Function

Enables RNA binding activity. Located in nucleoplasm

External Links
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Human
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SFARI Genomic Platforms
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Reports related to HNRNPUL2 (4 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 - Gillentine MA et al. (2021) Yes ADHD, epilepsy/seizures
3 Support - Woodbury-Smith M et al. (2022) Yes -
4 Recent Recommendation - Zhou X et al. (2022) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1015C>T p.Arg339Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.1216A>T p.Lys406Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.1351G>T p.Glu451Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.2077C>T p.Arg693Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.642C>A p.Tyr214Ter stop_gained De novo - - 33874999 Gillentine MA et al. (2021)
c.1522C>T p.Arg508Ter stop_gained Unknown - - 33874999 Gillentine MA et al. (2021)
c.1936C>T p.Arg646Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.834del p.Trp278CysfsTer10 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.2077del p.Arg693AspfsTer66 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1001dup p.Tyr334Ter frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.343G>A p.Glu115Lys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.971G>A p.Arg324His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2052_2053del p.Gly686LeufsTer3 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1829_1830del p.Tyr610TrpfsTer14 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1716del p.Arg572SerfsTer4 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1906del p.Ser636ProfsTer123 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.2141_2142del p.Tyr714LeufsTer70 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.2052_2053del p.Gly686LeufsTer3 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.1373del p.Val458GlyfsTer13 frameshift_variant Familial Paternal Multiplex 35982159 Zhou X et al. (2022)
c.829_830insGTCCCTTTGGTCTGGGGCAAGGA p.Leu277ProfsTer19 frameshift_variant Unknown Not maternal - 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.40852723004453

Ranking 22929/25841 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 0.99992539468351

Ranking 637/18225 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 0.93764165547847

Ranking 13593/18665 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 0.50827915985306

Ranking 461/20870 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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