Human Gene Module / Chromosome 7 / YWHAG

YWHAGtyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 14
Rare Variants / Common Variants
30 / 0
Aliases
YWHAG, 14-3-3GAMMA,  EIEE56,  PPP1R170
Associated Syndromes
Williams-Beuren syndrome
Chromosome Band
7q11.23
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the YWHAG gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Heterozygous variants in YWHAG are also responsible for a form of early infantile epileptic encephalopathy (EIEE56; OMIM 617665); in addition to early-onset seizures, intellectual disability and behavioral abnormalities including autism spectrum disorder have been observed in affected individuals (Guella et al., 2017; Kanani et al., 2020). YWHAG is located within the 7q11.23 chromosomal region associated with Williams-Beuren syndrome; Fusco et al., 2014 suggested that, based on genotype-phenotype correlation of deletions within this region, YWHAG haploinsufficiency may cause the severe neurological and neuropsychological deficits including epilepsy and autistic behavior observed in individuals with this syndrome.

Molecular Function

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. Both ablation and overexpression of YWHAG have been demonstrated to result in neuronal migration delay in the developing cerebral cortex (Wachi et al., 2016; Cornell et al., 2016).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to YWHAG (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits Fusco C , et al. (2013) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Ablation of the 14-3-3gamma Protein Results in Neuronal Migration Delay and Morphological Defects in the Developing Cerebral Cortex Wachi T , et al. (2015) No -
4 Support Overexpression of the 14-3-3gamma protein in embryonic mice results in neuronal migration delay in the developing cerebral cortex Cornell B , et al. (2016) No -
5 Support De Novo Mutations in YWHAG Cause Early-Onset Epilepsy Guella I , et al. (2017) No -
6 Recent recommendation Expanding the genotype-phenotype correlation of de novo heterozygous missense variants in YWHAG as a cause of developmental and epileptic encephalopathy Kanani F , et al. (2020) No -
7 Support - Brunet T et al. (2021) No -
8 Support - Pode-Shakked B et al. (2021) No -
9 Support - Mahjani B et al. (2021) Yes -
10 Support - Sanchis-Juan A et al. (2023) No -
11 Support - Ko YJ et al. (2023) No -
12 Support - Lucie Sedlackova et al. (2024) No -
13 Support - Erica Rosina et al. (2024) No -
14 Recent Recommendation - Valentina Cetica et al. (2024) No ASD, ADHD
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.44A>C p.Glu15Ala missense_variant De novo - - 28777935 Guella I , et al. (2017)
c.169C>G p.Arg57Gly missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.169C>T p.Arg57Cys missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.394C>T p.Arg132Cys missense_variant De novo - - 28777935 Guella I , et al. (2017)
c.394C>T p.Arg132Cys missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.398A>C p.Tyr133Ser missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.529C>A p.Leu177Ile missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.532A>G p.Asn178Asp missense_variant De novo - - 31926053 Kanani F , et al. (2020)
c.418G>A p.Gly140Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.169C>T p.Arg57Cys missense_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.148A>C p.Lys50Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.698G>A p.Trp233Ter stop_gained De novo - - 38491959 Valentina Cetica et al. (2024)
c.394C>T p.Arg132Cys missense_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.395G>A p.Arg132His missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.170G>A p.Arg57His missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.169C>T p.Arg57Cys missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.169C>T p.Arg57Cys missense_variant Unknown - - 38491959 Valentina Cetica et al. (2024)
c.170G>A p.Arg57His missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.387C>G p.Asp129Glu missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.394C>G p.Arg132Gly missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.394C>T p.Arg132Cys missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.394C>T p.Arg132Cys missense_variant Unknown - - 38491959 Valentina Cetica et al. (2024)
c.395G>A p.Arg132His missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.578C>T p.Ala193Val missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.619G>A p.Glu207Lys missense_variant De novo - - 38491959 Valentina Cetica et al. (2024)
c.619G>A p.Glu207Lys missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.169C>T p.Arg57Cys missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.148A>G p.Lys50Glu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.89dup p.Thr31AspfsTer5 frameshift_variant Familial Maternal - 38491959 Valentina Cetica et al. (2024)
c.187_188insC p.Ile63ThrfsTer3 frameshift_variant Familial Maternal Multiplex 38491959 Valentina Cetica et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

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.

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
3S

Increased from to 3S

Krishnan Probability Score

Score 0.51305613557836

Ranking 1799/25841 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 0.93761356881564

Ranking 2858/18225 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 0.69386608171997

Ranking 1119/18665 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 0.045284440268305

Ranking 7357/20870 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
CNVs associated with YWHAG(1 CNVs)
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7q11.23 82 Deletion-Duplication 112  /  450
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