rs141227274

chr15-77037068-C-T

Variant summary

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

The NM_003978.5(PSTPIP1):c.1143C>T(p.Ser381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,236 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.68

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=-0.83).
• BP6: Variant 15-77037068-C-T is Benign according to our data. Variant chr15-77037068-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 317186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77037068-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BS2: High AC in GnomAd at 245 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.1143C>T	p.Ser381=	synonymous_variant	15/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1143C>T	p.Ser381=	synonymous_variant	15/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00139 AC: 343 AN: 246630 Hom.: 1 AF XY: 0.00141 AC XY: 189 AN XY: 134512

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.00135 AC: 1973 AN: 1459972 Hom.: 4 Cov.: 31 AF XY: 0.00141 AC XY: 1026 AN XY: 726254

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00456

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.000779

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74450

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Apr 01, 2024	PSTPIP1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2023	- -
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. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.89
Dann	Benign	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: rs141227274; hg19: chr15-77329409;