rs139362350

chr15-77031194-A-Cchr15-77031194-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003978.5(PSTPIP1):c.657A>C(p.Gln219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,612,700 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q219Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.252

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009078503).
• BP6: Variant 15-77031194-A-C is Benign according to our data. Variant chr15-77031194-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 245667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 249 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.657A>C	p.Gln219His	missense_variant	10/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.657A>C	p.Gln219His	missense_variant	10/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000593 AC: 147 AN: 247912 Hom.: 1 AF XY: 0.000431 AC XY: 58 AN XY: 134662

Gnomad AFR exome AF: 0.00608

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1460368 Hom.: 0 Cov.: 30 AF XY: 0.000259 AC XY: 188 AN XY: 726362

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000828

Gnomad4 OTH exome AF: 0.000564

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74492

Gnomad4 AFR AF: 0.00534

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00438 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000702 AC: 85

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

PSTPIP1: BS1, BS2 -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.95	D;D;D;D
MetaRNN	Benign	0.0091	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.0	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D;D;D;D
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.78
MutPred		0.49		Loss of catalytic residue at Q219 (P = 0.2667);Loss of catalytic residue at Q219 (P = 0.2667);Loss of catalytic residue at Q219 (P = 0.2667);.;
MVP		0.56
MPC		0.59
ClinPred		0.058	T
GERP RS		-2.6
Varity_R		0.24
gMVP		0.64

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

Other links and lift over

dbSNP: rs139362350; hg19: chr15-77323535;