15-77032329-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_003978.5(PSTPIP1):c.773G>C(p.Gly258Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,612,608 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G258G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 26 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 55 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.94

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

pyogenic arthritis-pyoderma gangrenosum-acne syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
autoinflammatory syndrome
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndrome
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

PSTPIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_003978.5

BP4

Computational evidence support a benign effect (MetaRNN=0.007782966).

BP6

Variant 15-77032329-G-C is Benign according to our data. Variant chr15-77032329-G-C is described in ClinVar as Benign. ClinVar VariationId is 259211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1988/152376) while in subpopulation AFR AF = 0.0358 (1489/41584). AF 95% confidence interval is 0.0343. There are 26 homozygotes in GnomAd4. There are 915 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1988 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 link	c.773G>C	p.Gly258Ala	missense_variant	Exon 11 of 15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6 link	c.773G>C	p.Gly258Ala	missense_variant	Exon 11 of 15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1985

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.0276

Gnomad EAS

AF:

0.0192

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00820

AC:

2028

AN:

247418

AF XY:

0.00712

show subpopulations

Gnomad AFR exome

AF:

0.0325

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.0279

Gnomad EAS exome

AF:

0.0198

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.00948

GnomAD4 exome

AF:

0.00368

AC:

5377

AN:

1460232

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

2527

AN XY:

726400

show subpopulations

African (AFR)

AF:

0.0378

AC:

1264

AN:

33470

American (AMR)

AF:

0.0144

AC:

644

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

699

AN:

26124

East Asian (EAS)

AF:

0.0128

AC:

510

AN:

39698

South Asian (SAS)

AF:

0.00276

AC:

238

AN:

86254

European-Finnish (FIN)

AF:

0.000172

AC:

AN:

52174

Middle Eastern (MID)

AF:

0.0186

AC:

107

AN:

5762

European-Non Finnish (NFE)

AF:

0.00131

AC:

1458

AN:

1111712

Other (OTH)

AF:

0.00743

AC:

448

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

273

546

820

1093

1366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0130

AC:

1988

AN:

152376

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

915

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0358

AC:

1489

AN:

41584

American (AMR)

AF:

0.00862

AC:

132

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5190

South Asian (SAS)

AF:

0.00228

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00176

AC:

120

AN:

68040

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00461

Hom.:

Bravo

AF:

0.0154

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0272

AC:

114

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00772

AC:

932

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 21790734, 24233262, 23426477)

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PSTPIP1: BP4, BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Benign:3

Sep 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Autoinflammatory syndrome

Benign:1

Feb 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.14

T;.;.;T

Eigen

Benign

-0.013

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.13

T;T;T;T

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.;M;.

PhyloP100

1.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.0

Sift

Benign

0.76

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Vest4

0.45

ClinPred

0.018

GERP RS

5.0

PromoterAI

-0.0017

Neutral

(source)

Varity_R

0.055

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over