15-77032393-C-T

Variant names:

• chr15-77032393-C-T
• rs149195362
• ENST00000558870.1:c.76C>T

Variant summary

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

The ENST00000558870.1(PSTPIP1):​c.76C>T​(p.Arg26Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,612,612 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/8 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (26 hom.)
• Consequence: PSTPIP1 ENST00000558870.1 missense, splice_region
• Scores: Splicing: ADA: 0.00003305
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.13

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=-0.81).
• BP6: Variant 15-77032393-C-T is Benign according to our data. Variant chr15-77032393-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77032393-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 610 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.837C>T	p.Pro279Pro	splice_region_variant, synonymous_variant	Exon 11 of 15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.837C>T	p.Pro279Pro	splice_region_variant, synonymous_variant	Exon 11 of 15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 611 AN: 152254 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00382 AC: 943 AN: 247098 Hom.: 6 AF XY: 0.00382 AC XY: 515 AN XY: 134844

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.000602

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00416

GnomAD4 exome AF: 0.00400 AC: 5837 AN: 1460240 Hom.: 26 Cov.: 31 AF XY: 0.00392 AC XY: 2845 AN XY: 726430

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.00410

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152372 Hom.: 3 Cov.: 33 AF XY: 0.00444 AC XY: 331 AN XY: 74514

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0178

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00397 Hom.: 0

Bravo AF: 0.00246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PSTPIP1: BP4, BP7, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Oct 03, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autoinflammatory syndrome Benign:1

Feb 22, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.11
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.12		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: rs149195362; hg19: chr15-77324734; COSMIC: COSV51198386; COSMIC: COSV51198386;