chr15-77037132-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_003978.5(PSTPIP1):c.1207G>C(p.Gly403Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,612,100 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G403E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 3 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 9.21

Publications

10 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 15-77037132-G-C is Benign according to our data. Variant chr15-77037132-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440207.

BS2

High AC in GnomAd4 at 11 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003978.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PSTPIP1	NM_003978.5	MANE Select	c.1207G>C	p.Gly403Arg	missense	Exon 15 of 15	NP_003969.2
PSTPIP1	NM_001321137.1		c.1402G>C	p.Gly468Arg	missense	Exon 16 of 16	NP_001308066.1
PSTPIP1	NM_001411086.1		c.1198G>C	p.Gly400Arg	missense	Exon 15 of 15	NP_001398015.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.1207G>C	p.Gly403Arg	missense	Exon 15 of 15	ENSP00000452746.1
PSTPIP1	ENST00000559295.5	TSL:1	c.1150G>C	p.Gly384Arg	missense	Exon 14 of 14	ENSP00000452743.1
PSTPIP1	ENST00000558870.1	TSL:1	c.355G>C	p.Gly119Arg	missense	Exon 4 of 4	ENSP00000452779.1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000312

AC:

AN:

246962

AF XY:

0.000461

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000718

Gnomad OTH exome

AF:

0.000834

GnomAD4 exome

AF:

0.000187

AC:

273

AN:

1459852

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

726184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00176

AC:

152

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51946

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000720

AC:

AN:

1111640

Other (OTH)

AF:

0.000282

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000723

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000347

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000275

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Uncertain:2Benign:1

May 20, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 03, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PSTPIP1 c.1207G>C; p.Gly403Arg variant (rs369113632) has been published in the literature in an individual with pyoderma gangrenosum (Zeeli 2015). The variant is reported in the ClinVar database (Variation ID: 440207) and in the general population with an overall allele frequency of 0.03% (77/246,962 alleles, including 1 homozygote) in the Genome Aggregation Database. The glycine at codon 403 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.715). Due to limited information, the clinical significance of the p.Gly403Arg variant is uncertain at this time. References: Zeeli T et al. Pyoderma gangrenosum, acne and ulcerative colitis in a patient with a novel mutation in the PSTPIP1 gene. Clin Exp Dermatol. 2015 40(4):367-72. PMID: 25683018.

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autoinflammatory syndrome

Uncertain:1

Aug 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jul 27, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27464597, 25683018, 28593717)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.44

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.1

PhyloP100

9.2

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.91

MutPred

0.95

Gain of solvent accessibility (P = 0.0584)

MVP

0.92

MPC

0.69

ClinPred

0.26

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.59

gMVP

0.80

Mutation Taster

=6/94

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over