chr15-76997700-G-A

Variant names:

• chr15-76997700-G-A
• rs1022197
• NM_003978.5:c.36+2091G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003978.5(PSTPIP1):​c.36+2091G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 151,946 control chromosomes in the GnomAD database, including 7,692 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7692 hom., cov: 32)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 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.36+2091G>A		intron	N/A	NP_003969.2
	PSTPIP1	NM_001321137.1		c.231+2091G>A		intron	N/A	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.36+2091G>A		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.36+2091G>A		intron	N/A	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.36+2091G>A		intron	N/A	ENSP00000452743.1
	PSTPIP1	ENST00000559785.5	TSL:1	n.231+2091G>A		intron	N/A	ENSP00000452986.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44840 AN: 151828 Hom.: 7671 Cov.: 32

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.270

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.295 AC: 44889 AN: 151946 Hom.: 7692 Cov.: 32 AF XY: 0.301 AC XY: 22324 AN XY: 74252

African (AFR) AF: 0.433 AC: 17946 AN: 41408

American (AMR) AF: 0.372 AC: 5684 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 584 AN: 3464

East Asian (EAS) AF: 0.500 AC: 2578 AN: 5160

South Asian (SAS) AF: 0.323 AC: 1554 AN: 4812

European-Finnish (FIN) AF: 0.220 AC: 2323 AN: 10550

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13511 AN: 67972

Other (OTH) AF: 0.268 AC: 566 AN: 2112

Alfa AF: 0.271 Hom.: 1135

Bravo AF: 0.312

Asia WGS AF: 0.403 AC: 1400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.65
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1022197; hg19: chr15-77290041;