Human Gene Module / Chromosome 4 / FRYL

FRYLFRY like transcription coactivator

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
7 / 8
Rare Variants / Common Variants
27 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4p11
Associated Disorders
-
Relevance to Autism

Pan et al., 2024 reported 14 individuals with de novo heterozygous variants in the FRYL gene, including an ASD proband from the SPARK cohort, presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral problems (including a diagnosis of autism spectrum disorder in five individuals), dysmorphic facial features, and other congenital anomalies; subsequent modeling of four of the FRYL missense variants found in affected individuals in Drosophila identified three with severe or partial loss-of-function effects. Additional de novo variants in this gene, including a de novo splice-site variant and multiple de novo missense variants, have been identified in ASD probands (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015; Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022).

Molecular Function

Predicted to be involved in cell morphogenesis and neuron projection development. Predicted to be active in cell cortex and site of polarized growth.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FRYL (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) 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 Support - Zhou X et al. (2022) Yes -
7 Support - Cirnigliaro M et al. (2023) Yes -
8 Primary - Xueyang Pan et al. (2024) No ASD, ADHD, epilepsy/seizures
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2082T>G p.Ile694Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3865+1G>A - splice_site_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.7870A>G p.Thr2624Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5679C>A p.Ala1893= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.8619C>G p.Ala2873= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1987-1G>A - splice_site_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.3816C>T p.Ser1272= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4663C>T p.Arg1555Ter stop_gained De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.2096G>C p.Arg699Pro missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3014A>T p.Asp1005Val missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.7003T>A p.Ser2335Thr missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1141C>A p.Arg381Ser missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.7679G>A p.Arg2560Gln missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.328C>T p.Arg110Cys missense_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.8049A>C p.Glu2683Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2210_2211dup p.Ser738Ter stop_gained De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.4882T>C p.Phe1628Leu missense_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.6884T>C p.Phe2295Ser missense_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.8852A>G p.Tyr2951Cys missense_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.7190G>T p.Ser2397Ile missense_variant Unknown Not paternal - 38479391 Xueyang Pan et al. (2024)
c.1224del p.Lys409ArgfsTer15 frameshift_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.7571T>G p.Leu2524Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4724del p.Cys1575SerfsTer24 frameshift_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.1855_1858del p.Val619IlefsTer7 frameshift_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.1129_1130del p.Val377AsnfsTer24 frameshift_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.8079_8080del p.Gln2693HisfsTer4 frameshift_variant De novo - Simplex 38479391 Xueyang Pan et al. (2024)
c.5474_5475del p.Tyr1825CysfsTer22 frameshift_variant De novo - Simplex 38479391 Xueyang Pan 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."

4/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.49198630164579

Ranking 4847/25841 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 0.99999999250312

Ranking 131/18225 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 0.67616193315212

Ranking 1020/18665 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 0.17511785185306

Ranking 4710/20870 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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