15-77032304-G-C

Position:

• chr15-77032304-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_003978.5(PSTPIP1):​c.748G>C​(p.Glu250Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E250K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.45

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-77032304-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 15-77032304-G-C is Pathogenic according to our data. Variant chr15-77032304-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4434.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-77032304-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.748G>C	p.Glu250Gln	missense_variant	11/15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.748G>C	p.Glu250Gln	missense_variant	11/15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 250 of the PSTPIP1 protein (p.Glu250Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAPA syndrome (PMID: 11971877, 16527883, 20506269, 22161697). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4434). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSTPIP1 protein function. Experimental studies have shown that this missense change affects PSTPIP1 function (PMID: 11971877). This variant disrupts the p.Glu250 amino acid residue in PSTPIP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22161697, 22513199, 25845478, 26025129; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M;.;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.80
MutPred		0.79		Loss of phosphorylation at Y249 (P = 0.2602);Loss of phosphorylation at Y249 (P = 0.2602);Loss of phosphorylation at Y249 (P = 0.2602);.;
MVP		0.77
MPC		0.64
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

Other links and lift over

dbSNP: rs28939089; hg19: chr15-77324645;