rs121908130

Positions:

• chr15-77031225-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.669

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 15-77031225-G-A is Pathogenic according to our data. Variant chr15-77031225-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77031225-G-A is described in Lovd as [Pathogenic].

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: 1 AN: 1460706 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M;.;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N;N;N;N
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.093	T;T;T;T
Polyphen		0.40	B;.;P;.
Vest4		0.81
MutPred		0.89		Loss of catalytic residue at A230 (P = 0.0815);Loss of catalytic residue at A230 (P = 0.0815);Loss of catalytic residue at A230 (P = 0.0815);.;
MVP		0.71
MPC		0.16
ClinPred		0.91	D
GERP RS		2.6
Varity_R		0.083
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs121908130; hg19: chr15-77323566; COSMIC: COSV51198632; COSMIC: COSV51198632;