Human Gene Module / Chromosome 15 / FRMD5

FRMD5FERM domain containing 5

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
11 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
15q15.3
Associated Disorders
-
Relevance to Autism

Lyu et al., 2024 demonstrated that Frmd5-deficient mice displayed morphological abnormalities in neurons and synaptic dysfunction, learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior; tandem mass tag-labeled quantitative proteomics found that FRMD5 deletion affected the distribution of synaptic proteins implicated in ASD pathogenesis. De novo variants in the FRMD5 gene, including a de novo missense variant that was predicted to be deleterious and a de novo coding-synonymous variant, have been identified in ASD probands (Satterstrom et al., 2020; Zhou et al., 2022). Wilfert et al., 2021 identified FRMD5 as an ASD candidate gene based on the transmission of private likely gene-disruptive (LGD) variants exclusively to probands in two or more unrelated families. Lu et al., 2022 described eight probands with rare heterozygous missense variants in FRMD5 who presented with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement; one of these probands also presented with autism spectrum disorder. Additional functional characterization of six FRMD5 missense variants, including the c.1637A>G missense variant identified in the proband with ASD, in Drosophila in Lu et al., 2022 demonstrated partial loss-of-function effects.

Molecular Function

Enables integrin binding activity and protein kinase binding activity. Involved in negative regulation of cell motility; positive regulation of cell adhesion; and regulation of cell migration. Located in adherens junction.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FRMD5 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Wilfert AB et al. (2021) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Shenzhao Lu et al. (2022) No ASD, epilepsy/seizures
5 Primary - Tian-Jie Lyu et al. (2024) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1446G>A p.Leu482= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.340T>C p.Phe114Leu missense_variant De novo - - 36206744 Shenzhao Lu et al. (2022)
c.1051A>G p.Ser351Gly missense_variant De novo - - 36206744 Shenzhao Lu et al. (2022)
c.1053C>G p.Ser351Arg missense_variant De novo - - 36206744 Shenzhao Lu et al. (2022)
c.953G>A p.Arg318Gln missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1054T>C p.Cys352Arg missense_variant De novo - Simplex 36206744 Shenzhao Lu et al. (2022)
c.1060T>C p.Ser354Pro missense_variant De novo - Simplex 36206744 Shenzhao Lu et al. (2022)
c.1491del p.Phe497LeufsTer3 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.1637A>G p.Tyr546Cys missense_variant Unknown Not maternal Simplex 36206744 Shenzhao Lu et al. (2022)
c.1045A>C p.Ser349Arg missense_variant Unknown Not maternal Unknown 36206744 Shenzhao Lu et al. (2022)
c.1536_1539del p.Val514CysfsTer5 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
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 0.47949358351284

Ranking 8139/25841 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 0.99184316448602

Ranking 1722/18225 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 0.94556911423571

Ranking 16522/18665 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 0.13822790097902

Ranking 5390/20870 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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