rs1333618864

Variant names:

• chr15-77032353-A-C
• rs1333618864
• NM_003978.5:c.797A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-77032353-A-C
• chr15-77032353-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003978.5(PSTPIP1):​c.797A>C​(p.Asp266Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36388907).

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.797A>C	p.Asp266Ala	missense	Exon 11 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.992A>C	p.Asp331Ala	missense	Exon 12 of 16	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.797A>C	p.Asp266Ala	missense	Exon 11 of 15	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.797A>C	p.Asp266Ala	missense	Exon 11 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.797A>C	p.Asp266Ala	missense	Exon 11 of 14	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000558870.1	TSL:1	c.36A>C	p.Arg12Arg	synonymous	Exon 1 of 4	ENSP00000452779.1	H0YKF1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460316 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.4
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.26
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.61	P
Vest4		0.40
MutPred		0.48		Loss of helix (P = 0.1299)
MVP		0.55
MPC		0.19
ClinPred		0.96	D
GERP RS		5.0
PromoterAI		0.012	Neutral
Varity_R		0.26
gMVP		0.69
Mutation Taster		=64/36	polymorphism

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: rs1333618864; hg19: chr15-77324694;