rs28939089
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_003978.5(PSTPIP1):c.748G>A(p.Glu250Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E250Q) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
PSTPIP1
NM_003978.5 missense
NM_003978.5 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 6.45
Genes affected
PSTPIP1 (HGNC:9580): (proline-serine-threonine phosphatase interacting protein 1) This gene encodes a cytoskeletal protein that is highly expressed in hemopoietic tissues. This protein functions via its interaction with several different proteins involved in cytoskeletal organization and inflammatory processes. It binds to the cytoplasmic tail of CD2, an effector of T cell activation and adhesion, downregulating CD2-triggered adhesion. It binds PEST-type protein tyrosine phosphatases (PTP) and directs them to c-Abl kinase to mediate c-Abl dephosphorylation, thereby, regulating c-Abl activity. It also interacts with pyrin, which is found in association with the cytoskeleton in myeloid/monocytic cells and modulates immunoregulatory functions. Mutations in this gene are associated with PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. It is hypothesized that the disease-causing mutations compromise physiologic signaling necessary for the maintenance of a proper inflammatory response. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-77032304-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927
PP5
Variant 15-77032304-G-A is Pathogenic according to our data. Variant chr15-77032304-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77032304-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PSTPIP1 | NM_003978.5 | c.748G>A | p.Glu250Lys | missense_variant | 11/15 | ENST00000558012.6 | NP_003969.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PSTPIP1 | ENST00000558012.6 | c.748G>A | p.Glu250Lys | missense_variant | 11/15 | 1 | NM_003978.5 | ENSP00000452746.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Pathogenic:7Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
| not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust | Mar 23, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 28, 2019 | A heterozygous missense variant, NM_003978.3(PSTPIP1):c.748G>A, has been identified in exon 11 of 15 of the PSTPIP1 gene. The variant is predicted to result in a amino acid change from glutamic acid to lysine at position 250 of the protein (NP_003969.2(PSTPIP1):p.(Glu250Lys)). The glutamic acid at this position has conservation (100 vertebrates, UCSC), and is located within the BAR superfamily domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously reported pathogenic in multiple patients with hypercalprotectinemia and hyperzincemia (Hz/Hc) (Holzinger, D. et al., 2015). It has also been shown de novo in at least 8 patients and inherited in one family (Holzinger, D. et al., 2015). Additionally, studies demonstrated it impacts protein function (Holzinger, D. et al., 2015). A different variant in the same codon resulting in a change to glutamine is known to cause the classic phenotype, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) (Holzinger, D. et al., 2015). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 09, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5,PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 250 of the PSTPIP1 protein (p.Glu250Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PAPA syndrome or hyperzincemia and hypercalprotectinemia (PMID: 22161697, 22513199, 25845478, 26025129). ClinVar contains an entry for this variant (Variation ID: 97810). 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 expected to disrupt PSTPIP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Glu250 amino acid residue in PSTPIP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11971877, 16527883, 20506269, 22161697). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PS4+PM6_VeryStrong+PM5+PP4+PS3_Supporting - |
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 24, 2021 | PM2_supporting, PS2, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2022 | Published functional studies demonstrate altered function for E250K, with significantly increased binding to pyrin and an increase in phosphorylation by cABL, when compared to wild type (Holzinger et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22161697, 28628471, 29150835, 26989109, 25845478, 26025129, 28832562, 31119601, 32441320, 28960754, 33256319, 32054657, 29453417, 33597285, 22513199) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Hyperzincemia with functional zinc depletion Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;D;.
Vest4
MutPred
Gain of ubiquitination at E250 (P = 0.0198);Gain of ubiquitination at E250 (P = 0.0198);Gain of ubiquitination at E250 (P = 0.0198);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at