NM_003978.5:c.838+145A>G

Variant names:

• chr15-77032539-A-G
• rs4078354
• NM_003978.5:c.838+145A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003978.5(PSTPIP1):​c.838+145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 825,384 control chromosomes in the GnomAD database, including 167,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27462 hom., cov: 33)
  • Exomes 𝑓: 0.64 (140080 hom.)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.894
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-77032539-A-G is Benign according to our data. Variant chr15-77032539-A-G is described in ClinVar as Benign. ClinVar VariationId is 440205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

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.838+145A>G		intron	N/A	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1033+145A>G		intron	N/A	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.838+145A>G		intron	N/A	NP_001398015.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.838+145A>G		intron	N/A	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.872+111A>G		intron	N/A	ENSP00000452743.1
	PSTPIP1	ENST00000558870.1	TSL:1	c.77+145A>G		intron	N/A	ENSP00000452779.1

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90411 AN: 151946 Hom.: 27437 Cov.: 33

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.612

GnomAD2 exomes AF: 0.603 AC: 49589 AN: 82188 AF XY: 0.610

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.658

Gnomad NFE exome AF: 0.671

Gnomad OTH exome AF: 0.635

GnomAD4 exome AF: 0.641 AC: 431466 AN: 673320 Hom.: 140080 Cov.: 9 AF XY: 0.640 AC XY: 220453 AN XY: 344558

African (AFR) AF: 0.488 AC: 8188 AN: 16776

American (AMR) AF: 0.523 AC: 11888 AN: 22732

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 11085 AN: 16004

East Asian (EAS) AF: 0.528 AC: 16963 AN: 32102

South Asian (SAS) AF: 0.591 AC: 31338 AN: 53018

European-Finnish (FIN) AF: 0.652 AC: 22900 AN: 35112

Middle Eastern (MID) AF: 0.736 AC: 3035 AN: 4122

European-Non Finnish (NFE) AF: 0.662 AC: 304677 AN: 459916

Other (OTH) AF: 0.638 AC: 21392 AN: 33538

GnomAD4 genome AF: 0.595 AC: 90481 AN: 152064 Hom.: 27462 Cov.: 33 AF XY: 0.590 AC XY: 43840 AN XY: 74324

African (AFR) AF: 0.494 AC: 20474 AN: 41456

American (AMR) AF: 0.540 AC: 8261 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2415 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2486 AN: 5158

South Asian (SAS) AF: 0.561 AC: 2703 AN: 4820

European-Finnish (FIN) AF: 0.631 AC: 6678 AN: 10576

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.666 AC: 45270 AN: 67978

Other (OTH) AF: 0.612 AC: 1291 AN: 2110

Alfa AF: 0.641 Hom.: 76902

Bravo AF: 0.585

Asia WGS AF: 0.574 AC: 1996 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported.

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:1

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.63
PhyloP100		0.89
PromoterAI		0.038	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4078354; hg19: chr15-77324880; COSMIC: COSV51198084; COSMIC: COSV51198084;