rs11858480

Variant names:

• chr15-77032938-C-T
• rs11858480
• NM_003978.5:c.915C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003978.5(PSTPIP1):​c.915C>T​(p.Cys305Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,602,812 control chromosomes in the GnomAD database, including 817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (221 hom., cov: 33)
  • Exomes 𝑓: 0.021 (596 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.94

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-77032938-C-T is Benign according to our data. Variant chr15-77032938-C-T is described in ClinVar as [Benign]. Clinvar id is 259212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77032938-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.94 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.093 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.915C>T	p.Cys305Cys	synonymous_variant	Exon 12 of 15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.915C>T	p.Cys305Cys	synonymous_variant	Exon 12 of 15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6199 AN: 152134 Hom.: 221 Cov.: 33

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0280 AC: 6408 AN: 228940 Hom.: 173 AF XY: 0.0272 AC XY: 3392 AN XY: 124916

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.0632

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0301

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0211 AC: 30630 AN: 1450560 Hom.: 596 Cov.: 31 AF XY: 0.0213 AC XY: 15380 AN XY: 720466

Gnomad4 AFR exome AF: 0.0929

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.0701

Gnomad4 SAS exome AF: 0.0380

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0408 AC: 6211 AN: 152252 Hom.: 221 Cov.: 33 AF XY: 0.0408 AC XY: 3038 AN XY: 74438

Gnomad4 AFR AF: 0.0955

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0207

Gnomad4 EAS AF: 0.0634

Gnomad4 SAS AF: 0.0369

Gnomad4 FIN AF: 0.0288

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0257 Hom.: 67

Bravo AF: 0.0421

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs11858480; hg19: chr15-77325279;