rs200771233

Positions:

• chr15-77037076-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003978.5(PSTPIP1):​c.1151A>G​(p.Asp384Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,612,240 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (5 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.37

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067043245).
• BP6: Variant 15-77037076-A-G is Benign according to our data. Variant chr15-77037076-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 242305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77037076-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.1151A>G	p.Asp384Gly	missense_variant	15/15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1151A>G	p.Asp384Gly	missense_variant	15/15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152098 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00114 AC: 282 AN: 246980 Hom.: 2 AF XY: 0.00152 AC XY: 205 AN XY: 134654

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00713

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000684 AC: 998 AN: 1460026 Hom.: 5 Cov.: 31 AF XY: 0.000917 AC XY: 666 AN XY: 726276

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74442

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000439 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000478 AC: 4

ExAC AF: 0.00118 AC: 142

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 11, 2018	The PSTPIP1 c.1151A>G: p.Asp384Gly variant (rs200771233), to our knowledge, is not reported in the medical literature or in gene-specific databases. The variant is listed in the ClinVar database (Variation ID: 242305) and in the Genome Aggregation Database in 0.7% (221/30776 alleles, 2 homozygotes) of the South Asian population. The aspartic acid at this position is weakly conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Considering the increased allele frequency and the presence of homozygotes, this variant is considered likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PSTPIP1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.95	P;.;P
Vest4		0.84
MVP		0.88
MPC		0.72
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.37
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200771233; hg19: chr15-77329417;