rs35538044

Positions:

• chr15-77035914-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000558012.6(PSTPIP1):​c.1098G>A​(p.Ala366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,607,234 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: PSTPIP1 ENST00000558012.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.02

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-77035914-G-A is Benign according to our data. Variant chr15-77035914-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77035914-G-A is described in Lovd as [Benign]. Variant chr15-77035914-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.02 with no splicing effect.
• BS2: High AC in GnomAd4 at 714 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.1098G>A	p.Ala366=	synonymous_variant	14/15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1098G>A	p.Ala366=	synonymous_variant	14/15	1	NM_003978.5	ENSP00000452746	P3

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 714 AN: 152062 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00344 AC: 822 AN: 238662 Hom.: 3 AF XY: 0.00346 AC XY: 451 AN XY: 130230

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000821

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.000808

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00475 AC: 6912 AN: 1455054 Hom.: 20 Cov.: 34 AF XY: 0.00453 AC XY: 3279 AN XY: 723518

Gnomad4 AFR exome AF: 0.00468

Gnomad4 AMR exome AF: 0.00265

Gnomad4 ASJ exome AF: 0.000769

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000818

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00497

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.00464 AC XY: 345 AN XY: 74404

Gnomad4 AFR AF: 0.00542

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00440 Hom.: 2

Bravo AF: 0.00500

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PSTPIP1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autoinflammatory syndrome Benign:1

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	-0.84
CADD	Benign	0.026
DANN	Benign	0.40

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: rs35538044; hg19: chr15-77328255;