15-76995149-G-GCTGC

Position:

• chr15-76995149-G-GCTGC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003978.5(PSTPIP1):​c.-405_-402dupCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0739 in 1,170,486 control chromosomes in the GnomAD database, including 2,969 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (377 hom., cov: 28)
  • Exomes 𝑓: 0.075 (2592 hom.)
• Consequence: PSTPIP1 NM_003978.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.64

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 -16 ACMG points.

• BP6: Variant 15-76995149-G-GCTGC is Benign according to our data. Variant chr15-76995149-G-GCTGC is described in ClinVar as [Likely_benign]. Clinvar id is 317163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.-405_-402dupCCTG		5_prime_UTR_variant	1/15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012	c.-405_-402dupCCTG		5_prime_UTR_variant	1/15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10151 AN: 151682 Hom.: 377 Cov.: 28

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0791

Gnomad OTH AF: 0.0788

GnomAD4 exome AF: 0.0750 AC: 76386 AN: 1018692 Hom.: 2592 Cov.: 30 AF XY: 0.0749 AC XY: 36417 AN XY: 486106

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.0511

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.0652

Gnomad4 FIN exome AF: 0.0894

Gnomad4 NFE exome AF: 0.0771

Gnomad4 OTH exome AF: 0.0735

GnomAD4 genome AF: 0.0669 AC: 10158 AN: 151794 Hom.: 377 Cov.: 28 AF XY: 0.0684 AC XY: 5070 AN XY: 74170

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.0710

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.0658

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0791

Gnomad4 OTH AF: 0.0784

Bravo AF: 0.0647

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

- -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55909412; hg19: chr15-77287490;