Human Gene Module / Chromosome 19 / PPFIA3

PPFIA3PTPRF interacting protein alpha 3

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
25 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
19q13.33
Associated Disorders
-
Relevance to Autism

Paul et al., 2024 reported 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with a neurodevelopmental syndrome characterized by developmental delay, intellectual disability, hypotonia, dysmorphic features, microcephaly or macrocephaly, and epilepsy; a co-morbid diagnosis of autism spectrum disorder was reported in four of these individuals, while an additional five individuals presented with autistic features without a formal diagnosis of ASD. Additional de novo variants in the PPFIA3 gene, including three de novo missense variants and a de novo splice-region variant, have been identified in ASD probands (Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). Wilfert et al., 2021 identified PPFIA3 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.

Molecular Function

The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. Liprin family protein has been shown to localize phosphatase LAR to cell focal adhesions and may be involved in the molecular organization of presynaptic active zones. Wong et al., 2018 observed that Ppfia3 knockout mice generated by CRISPR/Cas9 gene editing exhibited reduced synaptic vesicle tethering and docking in hippocampal neurons, impaired synaptic vesicle exocytosis, and mild alterations in active zone structure.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPFIA3 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
2 Support - Man Yan Wong et al. (2018) No -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Wilfert AB et al. (2021) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Trost B et al. (2022) Yes -
7 Support - Kuokuo Li et al. (2024) Yes -
8 Primary - Maimuna S Paul et al. (2024) No ASD or autistic features, ADHD, epilepsy/seizures
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.739G>C p.Ala247Pro missense_variant De novo - - 36368308 Trost B et al. (2022)
c.3261G>A p.Leu1087= splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 38181735 Maimuna S Paul et al. (2024)
c.1243C>T p.Arg415Trp missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.2717C>T p.Ser906Leu missense_variant De novo - - 38181735 Maimuna S Paul et al. (2024)
c.2068G>A p.Asp690Asn missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.115C>T p.Arg39Cys missense_variant De novo - Simplex 38181735 Maimuna S Paul et al. (2024)
c.943G>T p.Ala315Ser missense_variant De novo - Simplex 38181735 Maimuna S Paul et al. (2024)
c.1243C>T p.Arg415Trp missense_variant De novo - Simplex 38181735 Maimuna S Paul et al. (2024)
c.1243C>T p.Arg415Trp missense_variant Unknown - Unknown 38181735 Maimuna S Paul et al. (2024)
c.1285C>T p.Arg429Trp missense_variant De novo - Unknown 38181735 Maimuna S Paul et al. (2024)
c.1638G>T p.Trp546Cys missense_variant De novo - Unknown 38181735 Maimuna S Paul et al. (2024)
c.1492C>T p.Arg498Trp missense_variant De novo - Multiplex 38181735 Maimuna S Paul et al. (2024)
c.2350C>T p.Arg784Trp missense_variant De novo - Multiplex 38181735 Maimuna S Paul et al. (2024)
c.745del p.Val249CysfsTer15 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.2374del p.Thr792HisfsTer14 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.732_739del p.Gln245ArgfsTer29 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.2276A>G p.Lys759Arg missense_variant Familial Paternal Unknown 38181735 Maimuna S Paul et al. (2024)
c.2377C>A p.Pro793Thr missense_variant Familial Maternal Unknown 38181735 Maimuna S Paul et al. (2024)
c.2706dup p.Ser903LeufsTer86 frameshift_variant Unknown - Unknown 38181735 Maimuna S Paul et al. (2024)
c.239A>C p.Gln80Pro missense_variant Unknown - Extended multiplex 38181735 Maimuna S Paul et al. (2024)
c.118G>A p.Glu40Lys missense_variant Unknown Not maternal Simplex 38181735 Maimuna S Paul et al. (2024)
c.240+1G>A - splice_site_variant Familial Maternal Extended multiplex 38181735 Maimuna S Paul et al. (2024)
c.3307del p.Glu1103AsnfsTer8 frameshift_variant Unknown - Multi-generational 38181735 Maimuna S Paul et al. (2024)
c.2609T>A p.Ile870Asn missense_variant De novo - Multiplex (monozygotic twins) 38181735 Maimuna S Paul 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 0.51193601016353

Ranking 1813/25841 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 0.99999959495107

Ranking 253/18225 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 0.94680626630982

Ranking 17019/18665 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 0.47086996033274

Ranking 739/20870 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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