15-77032539-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003978.5(PSTPIP1):c.838+145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 825,384 control chromosomes in the GnomAD database, including 167,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27462 hom., cov: 33)
  • Exomes 𝑓: 0.64 (140080 hom.)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.894

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-77032539-A-G is Benign according to our data. Variant chr15-77032539-A-G is described in ClinVar as [Benign]. Clinvar id is 440205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.838+145A>G		intron_variant		ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.838+145A>G		intron_variant		1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90411 AN: 151946 Hom.: 27437 Cov.: 33

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.612

GnomAD3 exomes AF: 0.603 AC: 49589 AN: 82188 Hom.: 15229 AF XY: 0.610 AC XY: 26202 AN XY: 42942

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.592

Gnomad FIN exome AF: 0.658

Gnomad NFE exome AF: 0.671

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.641 AC: 431466 AN: 673320 Hom.: 140080 Cov.: 9 AF XY: 0.640 AC XY: 220453 AN XY: 344558

Gnomad4 AFR exome AF: 0.488

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.591

Gnomad4 FIN exome AF: 0.652

Gnomad4 NFE exome AF: 0.662

Gnomad4 OTH exome AF: 0.638

GnomAD4 genome AF: 0.595 AC: 90481 AN: 152064 Hom.: 27462 Cov.: 33 AF XY: 0.590 AC XY: 43840 AN XY: 74324

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.540

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.482

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.666

Gnomad4 OTH AF: 0.612

Alfa AF: 0.656 Hom.: 44064

Bravo AF: 0.585

Asia WGS AF: 0.574 AC: 1996 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.9
Dann	Benign	0.63

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: rs4078354; hg19: chr15-77324880; COSMIC: COSV51198084; COSMIC: COSV51198084;