rs113386299

chr15-77018523-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003978.5(PSTPIP1):c.204G>A(p.Thr68=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,569,356 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (20 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.69

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-77018523-G-A is Benign according to our data. Variant chr15-77018523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 138818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00828 (1260/152258) while in subpopulation AFR AF= 0.0287 (1194/41534). AF 95% confidence interval is 0.0274. There are 12 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.204G>A	p.Thr68=	synonymous_variant	3/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.204G>A	p.Thr68=	synonymous_variant	3/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.00826 AC: 1257 AN: 152140 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00194 AC: 345 AN: 177612 Hom.: 9 AF XY: 0.00153 AC XY: 145 AN XY: 94946

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000418

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000426

GnomAD4 exome AF: 0.000886 AC: 1256 AN: 1417098 Hom.: 20 Cov.: 32 AF XY: 0.000738 AC XY: 517 AN XY: 700732

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.000198

Gnomad4 EAS exome AF: 0.0000532

Gnomad4 SAS exome AF: 0.0000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000606

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00828 AC: 1260 AN: 152258 Hom.: 12 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74452

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00405 Hom.: 2

Bravo AF: 0.00901

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2011

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	6.0
Dann	Benign	0.89

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: rs113386299; hg19: chr15-77310864;