rs201186216

Positions:

• chr15-77035870-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003978.5(PSTPIP1):​c.1054G>A​(p.Glu352Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,610,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. E352A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.20

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018837124).
• BP6: Variant 15-77035870-G-A is Benign according to our data. Variant chr15-77035870-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 317183.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.1054G>A	p.Glu352Lys	missense_variant	14/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1054G>A	p.Glu352Lys	missense_variant	14/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000330 AC: 81 AN: 245714 Hom.: 0 AF XY: 0.000358 AC XY: 48 AN XY: 134000

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000553

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000623

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.000233 AC: 340 AN: 1458564 Hom.: 0 Cov.: 34 AF XY: 0.000263 AC XY: 191 AN XY: 725516

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000511

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74380

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000294 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000367 AC: 44

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2022	The PSTPIP1 c.1054G>A; p.Glu352Lys variant (rs201186216) is reported in the literature in an individual affected with systemic auto-inflammatory disease (Rusmini 2016) but the variant was not determined to be causative. This variant is also reported in ClinVar (Variation ID: 317183) and is found in the general population with an allele frequency of 0.03% (83/277034 alleles) in the Genome Aggregation database. The glutamic acid at codon 352 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.078). Due to limited information, the clinical significance of the p.Glu352Lys variant is uncertain at this time. Reference: Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7. PMID: 26386126. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PSTPIP1: BP4 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2021

- -

PSTPIP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.97	N;N;N
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0090	B;.;B
Vest4		0.23
MVP		0.63
MPC		0.17
ClinPred		0.0047	T
GERP RS		3.6
Varity_R		0.088
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201186216; hg19: chr15-77328211;