rs529402949

Positions:

• chr15-77037059-G-A

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.1134G>A​(p.Leu378=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000548 in 1,612,220 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (3 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.42

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 (BayesDel_noAF=-0.6).
• BP6: Variant 15-77037059-G-A is Benign according to our data. Variant chr15-77037059-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77037059-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.1134G>A	p.Leu378=	synonymous_variant	15/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1134G>A	p.Leu378=	synonymous_variant	15/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00110 AC: 271 AN: 246542 Hom.: 1 AF XY: 0.00103 AC XY: 138 AN XY: 134456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00899

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.000518 AC: 756 AN: 1459918 Hom.: 3 Cov.: 31 AF XY: 0.000515 AC XY: 374 AN XY: 726228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00873

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000796

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00753

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000504 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PSTPIP1: BP4 -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.5
DANN	Benign	0.63

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: rs529402949; hg19: chr15-77329400;