15-77035914-G-A

Position:

chr15-77035914-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.02

Variant links:

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]

PSTPIP1 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.1098G>A	p.Ala366=	synonymous_variant	14/15	1	NM_003978.5	ENSP00000452746	P3	O43586-1

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

714

AN:

152062

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00346

AC XY:

451

AN XY:

130230

show subpopulations

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.:

Cov.:

AF XY:

0.00453

AC XY:

3279

AN XY:

723518

show subpopulations

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.:

Cov.:

AF XY:

0.00464

AC XY:

345

AN XY:

74404

show subpopulations

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.:

Bravo

AF:

0.00500

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over