PHLPP1PH domain and leucine rich repeat protein phosphatase 1
Autism Reports / Total Reports
7 / 7Rare Variants / Common Variants
10 / 0Aliases
-Associated Syndromes
-Chromosome Band
18q21.33Associated Disorders
-Relevance to Autism
Inherited loss-of-function (LoF) variants in the PHLPP1 gene were found to be exclusively transmitted to two ASD probands from two independent families (Wilfert et al., 2021), while additional de novo variants in this gene, including a de novo LoF variant, have also been reported in ASD probands (Zhou et al., 2022; Trost et al., 2022; More et al., 2023).
Molecular Function
This gene encodes a member of the serine/threonine phosphatase family. The encoded protein promotes apoptosis by dephosphorylating and inactivating the serine/threonine kinase Akt, and functions as a tumor suppressor in multiple types of cancer. Increased expression of this gene may also play a role in obesity and type 2 diabetes by interfering with Akt-mediated insulin signaling.
External Links
SFARI Genomic Platforms
Reports related to PHLPP1 (7 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | - | Wilfert AB et al. (2021) | Yes | - |
| 2 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
| 3 | Support | - | Zhou X et al. (2022) | Yes | - |
| 4 | Support | - | Trost B et al. (2022) | Yes | - |
| 5 | Support | - | More RP et al. (2023) | Yes | - |
| 6 | Support | - | Suhua Chang et al. () | Yes | - |
| 7 | Support | - | Soo-Whee Kim et al. (2024) | Yes | - |
Rare Variants (10)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.813G>A | p.Leu271= | synonymous_variant | De novo | - | - | 36368308 | Trost B et al. (2022) | |
| c.320C>T | p.Ala107Val | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.757G>T | p.Gly253Ter | stop_gained | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) | |
| c.4800C>T | p.Asn1600= | synonymous_variant | De novo | - | - | 39334436 | Soo-Whee Kim et al. (2024) | |
| c.4501G>A | p.Gly1501Arg | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.4527C>T | p.Ala1509= | synonymous_variant | De novo | - | Simplex | 39126614 | Suhua Chang et al. () | |
| c.967T>C | p.Ser323Pro | missense_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| c.1872del | p.Leu625Ter | frameshift_variant | De novo | - | Multiplex | 36702863 | More RP et al. (2023) | |
| c.78_119del | p.Ala27_Ala40del | inframe_deletion | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.2235_2238del | p.Asp745GlufsTer14 | frameshift_variant | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) |
Common Variants
No common variants reported.
SFARI Gene score
3
Suggestive Evidence
Score Delta: Score remained at 3
criteria met
See SFARI Gene'scoring criteriaThe 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.
4/1/2023
3
Increased from to 3
Krishnan Probability Score
Score 0.58675667723798
Ranking 505/25841 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 0.91815375718046
Ranking 3054/18225 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 0.86399920964528
Ranking 4021/18665 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 0.19082087370097
Ranking 4415/20870 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.