rs189773500

Positions:

chr15-77032931-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003978.5(PSTPIP1):c.908C>T(p.Pro303Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,604,630 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.504

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059553683).

BP6

Variant 15-77032931-C-T is Benign according to our data. Variant chr15-77032931-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77032931-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 linkuse as main transcript	c.908C>T	p.Pro303Leu	missense_variant	12/15	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.908C>T	p.Pro303Leu	missense_variant	12/15	1	NM_003978.5	ENSP00000452746	P3	O43586-1

Frequencies

GnomAD3 genomes

AF:

0.00268

AC:

408

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00922

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000667

AC:

155

AN:

232494

Hom.:

AF XY:

0.000433

AC XY:

AN XY:

126954

show subpopulations

Gnomad AFR exome

AF:

0.0101

Gnomad AMR exome

AF:

0.000511

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000572

Gnomad SAS exome

AF:

0.0000348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000958

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000271

AC:

393

AN:

1452368

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

154

AN XY:

721580

show subpopulations

Gnomad4 AFR exome

AF:

0.00912

Gnomad4 AMR exome

AF:

0.000731

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000650

GnomAD4 genome

AF:

0.00269

AC:

409

AN:

152262

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00922

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000843

Hom.:

Bravo

AF:

0.00326

ESP6500AA

AF:

0.0105

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000659

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2012

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. -

PSTPIP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.14

Sift

Benign

0.036

D;D

Sift4G

Benign

0.44

T;T

Polyphen

0.47

P;.

Vest4

0.25

MVP

0.73

MPC

0.15

ClinPred

0.020

GERP RS

4.8

Varity_R

0.052

gMVP

0.51

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