15-76995149-GCTGCCTGCCTGC-GCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTGC

Variant names:

• chr15-76995149-G-GCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTGC
• rs55909412
• NM_003978.5:c.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003978.5(PSTPIP1):​c.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,702 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSTPIP1 NM_003978.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• 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 0 ACMG points.

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.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_001411086.1		c.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_001398015.1	J3KPG6
	PSTPIP1	NM_001321136.2		c.-648_-647insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 16	NP_001308065.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559795.5	TSL:1	n.47_48insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		non_coding_transcript_exon	Exon 1 of 4
	PSTPIP1	ENST00000560223.5	TSL:1	n.-402_-401insCCTGCCTGCCTGCCTGCCTGCCTGCCTGCCTG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000454118.1	H0YNR2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151702 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000393 AC: 4 AN: 1018872 Hom.: 0 Cov.: 30 AF XY: 0.00000411 AC XY: 2 AN XY: 486202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21066

American (AMR) AF: 0.00 AC: 0 AN: 9720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9444

East Asian (EAS) AF: 0.00 AC: 0 AN: 11952

South Asian (SAS) AF: 0.00 AC: 0 AN: 53714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2288

European-Non Finnish (NFE) AF: 0.00000462 AC: 4 AN: 865754

Other (OTH) AF: 0.00 AC: 0 AN: 36368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151702 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 74056

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000699 Hom.: 85

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs55909412; hg19: chr15-77287490;