Human Gene Module / Chromosome 7 / EPHA1

EPHA1EPH receptor A1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 8
Rare Variants / Common Variants
11 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
7q34-q35
Associated Disorders
-
Relevance to Autism

De novo variants in the EPHA1 gene have been identified in ASD probands, including a de novo missense variant (p.Val567Ile) in a proband from the Simons Simplex Collection and two additional de novo missense variants in probands from the SPARK cohort and the Autism Sequencing Consortium (Iossifov et al., 2014; Sanders et al., 2015; Feliciano et al. 2019; Satterstrom et al., 2020), while inherited loss-of-function variants in this gene were observed in multiple ASD-affected siblings in two unrelated multiplex families from the iHART cohort (Ruzzo et al., 2019). Functional assessment of the ASD-associated p.Val567Ile missense variant in Drosophila using an overexpression-based strategy in Macrogliese et al., 2022 demonstrated that flies overexpressing EPHA1-p.Val567Ile presented with a phenotype of serrated wings of normal size, compared to the reduced wing-size and wing-margin serration phenotypes caused by the reference EPHA1 allele, indicating a partial loss-of-function effect.

Molecular Function

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene is expressed in some human cancer cell lines and has been implicated in carcinogenesis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EPHA1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1616-44C>T - intron_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.1712+19del - intron_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.335G>A p.Gly112Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.577G>A p.Ala193Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.577G>A p.Ala193Thr missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1052G>T p.Arg351Leu missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1923G>A p.Gly641%3D synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1699G>A p.Val567Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1519C>T p.Gln507Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2353G>T p.Gly785Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1189_1190insCCCGGGGG p.Arg397ProfsTer60 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
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.

4/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.36537690695189

Ranking 24042/25841 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 5.3036507434099E-11

Ranking 17000/18225 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 0.94688023979772

Ranking 17049/18665 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 -0.16420643765187

Ranking 14534/20870 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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