Human Gene Module / Chromosome 5 / P4HA2

P4HA2Prolyl 4-hydroxylase, alpha polypeptide II

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
5q31.1
Associated Disorders
-
Relevance to Autism

Three de novo missense variants in the P4HA2 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=1.21 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Molecular Function

This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis that catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to P4HA2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary 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 De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1327A>T p.Lys443Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.1365+1G>C p.? splice_site_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1189C>T p.Arg397Ter stop_gained Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.359G>A p.Arg120Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.871G>A p.Glu291Lys missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1048A>T p.Ile350Phe missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1382C>G p.Ala463Gly missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1382C>G p.Ala463Gly missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.458G>A p.Gly153Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.359G>A p.Arg120Gln missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1262A>G p.Tyr421Cys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1273G>T p.Gly425Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Three de novo missense variants in the P4HA2 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=1.21 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Three de novo missense variants in the P4HA2 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=1.21 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Three de novo missense variants in the P4HA2 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=1.21 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
1/1/2016
icon
3

Increased from to 3

Description

Three de novo missense variants in the P4HA2 gene have been identified in simplex ASD cases, with no de novo events in this gene observed in 1,786 unaffected siblings from the Simons Simplex Collection (P=1.21 x 10-4) (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015).

Krishnan Probability Score

Score 0.093411679894529

Ranking 25748/25841 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 6.4612841107469E-5

Ranking 13326/18225 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 0.68945642996236

Ranking 1093/18665 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 -0.21699228934601

Ranking 15774/20870 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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