rs28939089

Variant names:

Your query was ambiguous. Multiple possible variants found:

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 6.45

Variant links:

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]

PSTPIP1 links:

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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 rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 link	c.748G>A	p.Glu250Lys	missense_variant	Exon 11 of 15	ENST00000558012.6	NP_003969.2	O43586-1A0A0S2Z5P3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6 link	c.748G>A	p.Glu250Lys	missense_variant	Exon 11 of 15	1	NM_003978.5	ENSP00000452746.1		O43586-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 23, 2023

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5,PP3. -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PM6_VeryStrong+PM5+PP4+PS3_Supporting -

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 24, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PS2, PS4 -

Feb 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Hyperzincemia and hypercalprotectinemia

Pathogenic:1

Sep 23, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.;.;T

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

3.1

M;.;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.90

MutPred

0.84

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

0.77

MPC

0.69

ClinPred

0.99

GERP RS

5.0

Varity_R

0.68

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over