ENST00000558870.1:c.76C>G

Variant names:

• chr15-77032392-C-G
• ENST00000559295.5:c.836C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000558870.1(PSTPIP1):​c.75C>G​(p.Pro25Pro) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000685 in 1,460,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSTPIP1 ENST00000558870.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.4410
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000558870.1. 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.836C>G	p.Pro279Arg	missense splice_region	Exon 11 of 15	NP_003969.2
	PSTPIP1	NM_001321135.2		c.836C>G	p.Pro279Arg	missense	Exon 11 of 14	NP_001308064.1	O43586-2
	PSTPIP1	NM_001321137.1		c.1031C>G	p.Pro344Arg	missense splice_region	Exon 12 of 16	NP_001308066.1	O43586

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000559295.5	TSL:1	c.836C>G	p.Pro279Arg	missense	Exon 11 of 14	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.836C>G	p.Pro279Arg	missense splice_region	Exon 11 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000558870.1	TSL:1	c.75C>G	p.Pro25Pro	splice_region synonymous	Exon 1 of 4	ENSP00000452779.1	H0YKF1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460252 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726428

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.34		Loss of catalytic residue at P278 (P = 0.0103)
MVP		0.87
MPC		0.66
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.88
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.070		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

hg19: chr15-77324733;