Human Gene Module / Chromosome 16 / SLC7A5

SLC7A5solute carrier family 7 member 5

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
7 / 0
Aliases
SLC7A5, 4F2LC,  CD98,  D16S469E,  E16,  LAT1,  MPE16
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
16q24.2
Associated Disorders
-
Relevance to Autism

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

Molecular Function

The SLC7A5 gene encodes for a sodium-independent, high-affinity transport of large neutral amino acids such as phenylalanine, tyrosine, leucine, arginine and tryptophan.

Reports related to SLC7A5 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder Tafrlungeanu DC , et al. (2016) Yes -
2 Support Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations Baronas VA , et al. (2018) No -
3 Support Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder Cascio L , et al. (2019) Yes -
4 Support The amino acid transporter Slc7a5 regulates the mTOR pathway and is required for granule cell development Sokolov AM et al. (2020) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.816-18C>T - intron_variant De novo NA - 31701662 Cascio L , et al. (2019)
c.1290+44G>A - intron_variant De novo NA - 31701662 Cascio L , et al. (2019)
c.690C>G p.Asn230Lys missense_variant Unknown - - 31701662 Cascio L , et al. (2019)
c.1123C>A p.Pro375Thr missense_variant De novo NA - 31701662 Cascio L , et al. (2019)
c.690C>G p.Asn230Lys missense_variant - Both parents - 31701662 Cascio L , et al. (2019)
c.1124C>T p.Pro375Leu missense_variant Familial Both parents Multiplex 27912058 Tafrlungeanu DC , et al. (2016)
c.737C>T p.Ala246Val missense_variant Familial Both parents Extended multiplex 27912058 Tafrlungeanu DC , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

Score Delta: Score remained at 3

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.

7/1/2020
3
icon
3

Score remained at 3

Description

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

1/1/2017
icon
3

Increased from to 3

Description

Deletion of Slc7a5 from the endothelial cells of the blood-brain barrier in mice resulted in an atypical amino acid profile in the brain, abnormal mRNA translation, reduced mIPSC frequency in pyramidal neurons of the somatosensory cortex and cerebellar Purkinje cells, decreased exploratory behavior and locomotion, and abnormalities in social interaction (Tarlungeanu et al., 2016). In the same report, homozygous loss-of-function missense variants in the SLC7A5 gene were identified in two consanguineous families with affected individuals displaying ASD, delays in gross motor, fine motor, and social milestones, delayed or absent language development, and microcephaly or seizures.

Krishnan Probability Score

Score 0.44730100349286

Ranking 12853/25841 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.
ExAC Score

Score 0.50849659951407

Ranking 5409/18225 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
Sanders TADA Score

Score 0.86361684500944

Ranking 4004/18665 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).
Zhang D Score

Score -0.028859224668259

Ranking 9650/20870 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.
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