Human Gene Module / Chromosome 1 / ABL2

ABL2ABL proto-oncogene 2, non-receptor tyrosine kinase

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 10
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q25.2
Associated Disorders
-
Relevance to Autism

Rare de novo variants in the ABL2 gene have been identified in ASD probands, including a de novo missense variant (p.Ala1099Thr) in a proband from the Simons Simplex Collection (Iossifov et al., 2014; Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020), while an maternally-inherited loss-of-function variant in this gene was observed in all four ASD-affected siblings from a multiplex family from the iHART cohort (Ruzzo et al., 2019). Functional assessment of the ASD-associated p.Ala1099Thr missense variant in Drosophila using a rescue-based strategy in Macrogliese et al., 2022 demonstrated that humanized flies carrying the ABL2-p.Ala1099Thr mutation had significantly decreased lifespan compared with reference animals, indicating a reduced ability to rescue TG4 lethality that was consistent with a loss-of-function effect. Previous studies have shown that genetic knock-out of this gene in mice resulted in synapse, dendritic spine, and dendrite arbor loss accompanied by behavioral deficits (Moresco et al., 2005; Sfakianos et al., 2007).

Molecular Function

This gene encodes a member of the Abelson family of nonreceptor tyrosine protein kinases. The protein is highly similar to the c-abl oncogene 1 protein, including the tyrosine kinase, SH2 and SH3 domains, and it plays a role in cytoskeletal rearrangements through its C-terminal F-actin- and microtubule-binding sequences. This gene is expressed in both normal and tumor cells, and is involved in translocation with the ets variant 6 gene in leukemia.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to ABL2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Moresco EM et al. (2005) No -
2 Support - Sfakianos MK et al. (2007) No -
3 Support - Lin YC et al. (2013) No -
4 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
9 Support - Shaw JE et al. (2021) No -
10 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.157+24183T>C - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.158-46916A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.392-869C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.*3602A>G - 3_prime_UTR_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.157+42429A>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.158-35147A>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.*6317C>T - 3_prime_UTR_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3295G>A p.Ala1099Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.758A>G p.Asp253Gly missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2826del p.Pro943GlnfsTer36 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.44885417393418

Ranking 11387/25841 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 0.0097025768739759

Ranking 10025/18225 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 0.93841466986263

Ranking 13855/18665 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 0.55183364503613

Ranking 239/20870 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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