chr15-77031225-G-A

Variant names:

• chr15-77031225-G-A
• rs121908130
• NM_003978.5:c.688G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_003978.5(PSTPIP1):​c.688G>A​(p.Ala230Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,706 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000820801: Experimental studies have shown that this missense change affects PSTPIP1 function (PMID:11971877, 14595024, 19934105, 20506269)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A230A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.669
• Publications: 49 publications found

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: Orphanet, G2P, 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000820801: Experimental studies have shown that this missense change affects PSTPIP1 function (PMID: 11971877, 14595024, 19934105, 20506269).; SCV001468468: "In vitro and in vivo (mouse) functional studies support that this variant will impact the protein, suggesting impaired binding to PTP-PEST (Wise 2002 PMID:11971877, Cortesio 2010 PMID:20506269, Wang 2013 PMID:23293022)."; SCV000514293: Published functional studies demonstrate increased pyrin binding and hyperphosphorylation as well as increased IL-1b secretion (Wang et al., 2013; Samukawa et al., 2021); SCV004108050: Yeast two-hybrid assays showed that this variant lead to severely reduced binding ability of the protein (Wise et al. 2002. PubMed ID: 11971877). Additional function studies showed that this variant lead to defects in mononuclear cell podosome formation and migration of macrophages (Cortesio et al. 2010. PubMed ID: 20506269).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 15-77031225-G-A is Pathogenic according to our data. Variant chr15-77031225-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.688G>A	p.Ala230Thr	missense	Exon 10 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.883G>A	p.Ala295Thr	missense	Exon 11 of 16	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.688G>A	p.Ala230Thr	missense	Exon 10 of 15	NP_001398015.1	J3KPG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.688G>A	p.Ala230Thr	missense	Exon 10 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.688G>A	p.Ala230Thr	missense	Exon 10 of 14	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000559785.5	TSL:1	n.883G>A		non_coding_transcript_exon	Exon 11 of 16	ENSP00000452986.1	H0YKY3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460706 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726566

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111636

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000408 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
4	-	-	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (4)
1	-	-	PSTPIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.67
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.093	T
Polyphen		0.40	B
Vest4		0.81
MutPred		0.89		Loss of catalytic residue at A230 (P = 0.0815)
MVP		0.71
MPC		0.16
ClinPred		0.91	D
GERP RS		2.6
Varity_R		0.083
gMVP		0.40
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908130; hg19: chr15-77323566; COSMIC: COSV51198632; COSMIC: COSV51198632;