NM_003978.5:c.1098G>A

Variant names:

• chr15-77035914-G-A
• rs35538044
• NM_003978.5:c.1098G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003978.5(PSTPIP1):​c.1098G>A​(p.Ala366Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,607,234 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.02
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-77035914-G-A is Benign according to our data. Variant chr15-77035914-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.02 with no splicing effect.
• BS2: High AC in GnomAd4 at 714 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.1098G>A	p.Ala366Ala	synonymous	Exon 14 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1293G>A	p.Ala431Ala	synonymous	Exon 15 of 16	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.1089G>A	p.Ala363Ala	synonymous	Exon 14 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.1098G>A	p.Ala366Ala	synonymous	Exon 14 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.1041G>A	p.Ala347Ala	synonymous	Exon 13 of 14	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000558870.1	TSL:1	c.246G>A	p.Ala82Ala	synonymous	Exon 3 of 4	ENSP00000452779.1	H0YKF1

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 714 AN: 152062 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00344 AC: 822 AN: 238662 AF XY: 0.00346

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000821

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.00491

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00475 AC: 6912 AN: 1455054 Hom.: 20 Cov.: 34 AF XY: 0.00453 AC XY: 3279 AN XY: 723518

African (AFR) AF: 0.00468 AC: 156 AN: 33360

American (AMR) AF: 0.00265 AC: 117 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.000769 AC: 20 AN: 26012

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39558

South Asian (SAS) AF: 0.000818 AC: 70 AN: 85602

European-Finnish (FIN) AF: 0.00475 AC: 242 AN: 50990

Middle Eastern (MID) AF: 0.00325 AC: 16 AN: 4918

European-Non Finnish (NFE) AF: 0.00539 AC: 5990 AN: 1110330

Other (OTH) AF: 0.00497 AC: 299 AN: 60114

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152180 Hom.: 1 Cov.: 32 AF XY: 0.00464 AC XY: 345 AN XY: 74404

African (AFR) AF: 0.00542 AC: 225 AN: 41524

American (AMR) AF: 0.00674 AC: 103 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4812

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 67998

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00458 Hom.: 3

Bravo AF: 0.00500

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (3)
-	-	2	not specified (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.026
DANN	Benign	0.40
PhyloP100		-4.0
Mutation Taster		=99/1	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: rs35538044; hg19: chr15-77328255;