15-77028566-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003978.5(PSTPIP1):c.430T>G(p.Tyr144Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y144N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 link	c.430T>G	p.Tyr144Asp	missense_variant	Exon 7 of 15	ENST00000558012.6	NP_003969.2	O43586-1A0A0S2Z5P3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6 link	c.430T>G	p.Tyr144Asp	missense_variant	Exon 7 of 15	1	NM_003978.5	ENSP00000452746.1		O43586-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449338

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.00

AC:

AN:

42924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

38940

South Asian (SAS)

AF:

0.00

AC:

AN:

84192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106934

Other (OTH)

AF:

0.00

AC:

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Uncertain:1

May 10, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PSTPIP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with aspartic acid at codon 144 of the PSTPIP1 protein (p.Tyr144Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

D;.;.;.;.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.1

M;.;.;M;.;.

PhyloP100

6.2

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-9.1

D;D;D;D;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.99

D;.;.;D;.;.

Vest4

0.95

MutPred

0.56

Gain of ubiquitination at K141 (P = 0.0303);Gain of ubiquitination at K141 (P = 0.0303);Gain of ubiquitination at K141 (P = 0.0303);Gain of ubiquitination at K141 (P = 0.0303);.;.;

MVP

0.90

MPC

0.88

ClinPred

1.0

GERP RS

4.5

Varity_R

0.92

gMVP

0.77

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over