15-77037076-A-G

Variant names:

• chr15-77037076-A-G
• rs200771233
• NM_003978.5:c.1151A>G

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D384N) has been classified as Uncertain significance.

• 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
• Publications: 4 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 242305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 75 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.1151A>G	p.Asp384Gly	missense	Exon 15 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1346A>G	p.Asp449Gly	missense	Exon 16 of 16	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.1142A>G	p.Asp381Gly	missense	Exon 15 of 15	NP_001398015.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.1151A>G	p.Asp384Gly	missense	Exon 15 of 15	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.1094A>G	p.Asp365Gly	missense	Exon 14 of 14	ENSP00000452743.1
	PSTPIP1	ENST00000558870.1	TSL:1	c.299A>G	p.Asp100Gly	missense	Exon 4 of 4	ENSP00000452779.1

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

GnomAD2 exomes AF: 0.00114 AC: 282 AN: 246980 AF XY: 0.00152

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00738 AC: 637 AN: 86256

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52040

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5762

European-Non Finnish (NFE) AF: 0.000220 AC: 245 AN: 1111634

Other (OTH) AF: 0.000845 AC: 51 AN: 60334

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

African (AFR) AF: 0.000169 AC: 7 AN: 41524

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68000

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000381 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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PSTPIP1: BS2

Jun 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.067	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.95	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
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs200771233; hg19: chr15-77329417;