rs189773500

Variant names:

• chr15-77032931-C-T
• rs189773500
• NM_003978.5:c.908C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003978.5(PSTPIP1):​c.908C>T​(p.Pro303Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,604,630 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P303T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.504
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059553683).
• BP6: Variant 15-77032931-C-T is Benign according to our data. Variant chr15-77032931-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 409 Unknown,AD gene.

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.908C>T	p.Pro303Leu	missense	Exon 12 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1103C>T	p.Pro368Leu	missense	Exon 13 of 16	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.908C>T	p.Pro303Leu	missense	Exon 12 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.908C>T	p.Pro303Leu	missense	Exon 12 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.872+503C>T		intron	N/A	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000558870.1	TSL:1	c.77+537C>T		intron	N/A	ENSP00000452779.1	H0YKF1

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152144 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00922

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000667 AC: 155 AN: 232494 AF XY: 0.000433

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000958

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000271 AC: 393 AN: 1452368 Hom.: 2 Cov.: 31 AF XY: 0.000213 AC XY: 154 AN XY: 721580

African (AFR) AF: 0.00912 AC: 304 AN: 33326

American (AMR) AF: 0.000731 AC: 32 AN: 43784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51490

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108072

Other (OTH) AF: 0.000650 AC: 39 AN: 59988

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152262 Hom.: 3 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74438

African (AFR) AF: 0.00922 AC: 383 AN: 41542

American (AMR) AF: 0.00131 AC: 20 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00137 Hom.: 3

Bravo AF: 0.00326

ESP6500AA AF: 0.0105 AC: 41

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000659 AC: 79

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (3)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	PSTPIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.50
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Benign	0.036	D
Sift4G	Benign	0.44	T
Polyphen		0.47	P
Vest4		0.25
MVP		0.73
MPC		0.15
ClinPred		0.020	T
GERP RS		4.8
Varity_R		0.052
gMVP		0.51
Mutation Taster		=97/3	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: rs189773500; hg19: chr15-77325272;