rs201572812

Positions:

• chr15-77037133-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_003978.5(PSTPIP1):​c.1208G>A​(p.Gly403Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,612,012 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G403R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (3 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.40

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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.1208G>A	p.Gly403Glu	missense_variant	15/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1208G>A	p.Gly403Glu	missense_variant	15/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 52 AN: 246996 Hom.: 0 AF XY: 0.000275 AC XY: 37 AN XY: 134638

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000487 AC: 711 AN: 1459860 Hom.: 3 Cov.: 31 AF XY: 0.000464 AC XY: 337 AN XY: 726178

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000385

Gnomad4 NFE exome AF: 0.000594

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74328

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000225 AC: 27

EpiCase AF: 0.000709

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The PSTPIP1 c.1208G>A; p.Gly403Glu variant (rs201572812), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 242306). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (52/126858 alleles) in the Genome Aggregation Database. The glycine at codon 403 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly403Arg) has been reported in an individual with pyoderma gangrenosum, acne and ulcerative colitis, although its clinical significance in this individual was not demonstrated (Zeeli 2015). Due to limited information, the clinical significance of the p.Gly403Glu variant is uncertain at this time. References: Zeeli T et al. Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene. Clin Exp Dermatol. 2015 Jun;40(4):367-72. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 403 of the PSTPIP1 protein (p.Gly403Glu). This variant is present in population databases (rs201572812, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PSTPIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 242306). 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 with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2016

The G403E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G403E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the SH3 region that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same codon (G403R) has been reported in the Human Gene Mutation Database in association with pyoderma gangrenosum, acne, and ulcerative colitis (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the pathogenicity of missense changes in the SH3 region of the PSTPIP1 protein is unclear, as pathogenic variants associated with PAPA syndrome have traditionally been identified in the coiled-coil domain region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 08, 2021

- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D;D;D
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.83
MVP		0.90
MPC		0.73
ClinPred		0.56	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.66
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201572812; hg19: chr15-77329474; COSMIC: COSV51204048; COSMIC: COSV51204048;