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
Entrez GeneOMIMUniProtHumanBaseVariCarta
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= 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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