rs121908130
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_003978.5(PSTPIP1):c.688G>A(p.Ala230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A230A) has been classified as Likely benign.
Frequency
Consequence
NM_003978.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSTPIP1 | NM_003978.5 | c.688G>A | p.Ala230Thr | missense_variant | 10/15 | ENST00000558012.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSTPIP1 | ENST00000558012.6 | c.688G>A | p.Ala230Thr | missense_variant | 10/15 | 1 | NM_003978.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460706Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726566
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2023 | Published functional studies demonstrate increased pyrin binding and hyperphosphorrylation as well as increased IL-1b secretion (Wang et al., 2013; Samukawa et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16738958, 21438098, 24421327, 25040622, 26025129, 23426477, 17213252, 21790734, 25845478, 22878270, 35152348, 20506269, 34880353, 34262554, 34620178, 19934105, 34745107, 33218716, 28696038, 33338535, 34492165, 29148036, 34435004, 28236224, 35840971, 31471736, 28421071, 19673875, 15580218, 22513199, 28243699, 31139187, 11971877, 21325428, 22161697, 30467586, 34938582, 14595024, 17964261, 19584923, 23293022) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSTPIP1 function (PMID: 11971877, 14595024, 19934105, 20506269). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PSTPIP1 protein function. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 230 of the PSTPIP1 protein (p.Ala230Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) (PMID: 11971877, 15580218, 19673875, 22161697, 22513199, 26025129). It has also been observed to segregate with disease in related individuals. This variant is also known as c.904G>A. ClinVar contains an entry for this variant (Variation ID: 4435). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 15, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | PSTPIP1 NM_003978.4 exon 10 .pAla230Thr (c.688G>A): This variant has been reported in the literature in at least 5 individuals with Pyogenic Arthritis, Pyoderma gangrenosum and Acne syndrome (PAPA), segregating with disease in 10 affected family members (Wise 2002 PMID:11971877, Cortesio 2010 PMID:20506269, Demidowich 2012 PMID:22161697, Schaffler 2019 PMID:30467586). This variant is not present in large control databases. This variant is present in ClinVar, with two labs classifying this variant as pathogenic (Variation ID:4435). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In vitro and in vivo (mouse) functional studies support that this variant will impact the protein, suggesting impaired binding to PTP-PEST (Wise 2002 PMID:11971877, Cortesio 2010 PMID:20506269, Wang 2013 PMID:23293022). In summary, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
PSTPIP1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 18, 2022 | The PSTPIP1 c.688G>A variant is predicted to result in the amino acid substitution p.Ala230Thr. In the literature, this variant is also referred to as 904G>A or G904A. This variant has been reported in individuals with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (Wise et al. 2002. PubMed ID: 11971877; Cortesio et al. 2010. PubMed ID: 20506269; Demidowich et al. 2011. PubMed ID: 22161697). Of note, this variant was shown to segregate with disease in affected families (Wise et al. 2002. PubMed ID: 11971877). Yeast two-hybrid assays showed that this variant lead to severely reduced binding ability of the protein (Wise et al. 2002. PubMed ID: 11971877). Additional function studies showed that this variant lead to defects in mononuclear cell podosome formation and migration of macrophages (Cortesio et al. 2010. PubMed ID: 20506269). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/4435/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at