rs145344175

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003978.5(PSTPIP1):c.1144G>A(p.Ala382Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,612,252 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 6 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.25

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008904904).

BP6

Variant 15-77037069-G-A is Benign according to our data. Variant chr15-77037069-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 317187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77037069-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000467 (682/1459964) while in subpopulation AFR AF= 0.0165 (554/33476). AF 95% confidence interval is 0.0154. There are 6 homozygotes in gnomad4_exome. There are 301 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 675 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 linkuse as main transcript	c.1144G>A	p.Ala382Thr	missense_variant	15/15	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.1144G>A	p.Ala382Thr	missense_variant	15/15	1	NM_003978.5	ENSP00000452746	P3	O43586-1

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

674

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000735

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00104

AC:

257

AN:

246706

Hom.:

AF XY:

0.000714

AC XY:

AN XY:

134524

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000467

AC:

682

AN:

1459964

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

726248

show subpopulations

Gnomad4 AFR exome

AF:

0.0165

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.00443

AC:

675

AN:

152288

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

319

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0156

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000673

Hom.:

Bravo

AF:

0.00525

ESP6500AA

AF:

0.0119

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00122

AC:

147

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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 25, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2021	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autoinflammatory syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.85

D;T;T

MetaRNN

Benign

0.0089

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.022

Sift

Benign

0.44

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.046

B;.;B

Vest4

0.11

MVP

0.43

MPC

0.15

ClinPred

0.0058

GERP RS

3.6

Varity_R

0.049

gMVP

0.27

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