15-77022791-C-T

Variant names:

• chr15-77022791-C-T
• rs3936040
• NM_003978.5:c.213-2493C>T

Variant summary

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

The NM_003978.5(PSTPIP1):​c.213-2493C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,152 control chromosomes in the GnomAD database, including 2,474 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 0.18 (2474 hom., cov: 33)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.197 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.213-2493C>T		intron	N/A	NP_003969.2
	PSTPIP1	NM_001321137.1		c.408-2493C>T		intron	N/A	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.213-2493C>T		intron	N/A	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.213-2493C>T		intron	N/A	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.213-2493C>T		intron	N/A	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000559785.5	TSL:1	n.408-2493C>T		intron	N/A	ENSP00000452986.1	H0YKY3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26865 AN: 152034 Hom.: 2469 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.177 AC: 26889 AN: 152152 Hom.: 2474 Cov.: 33 AF XY: 0.176 AC XY: 13086 AN XY: 74376

African (AFR) AF: 0.149 AC: 6197 AN: 41506

American (AMR) AF: 0.152 AC: 2319 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3470

East Asian (EAS) AF: 0.120 AC: 620 AN: 5174

South Asian (SAS) AF: 0.208 AC: 1001 AN: 4820

European-Finnish (FIN) AF: 0.186 AC: 1973 AN: 10582

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13488 AN: 67984

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.187 Hom.: 1195

Bravo AF: 0.170

Asia WGS AF: 0.196 AC: 680 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.35
PhyloP100		-1.5
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: rs3936040; hg19: chr15-77315132;