15-76995149-GCTGCCTGCCTGC-GCTGCCTGCCTGCCTGC

Variant names:

• chr15-76995149-G-GCTGC
• rs55909412
• NM_003978.5:c.-405_-402dupCCTG

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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.-405_-402dupCCTG		5_prime_UTR	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_001411086.1		c.-405_-402dupCCTG		5_prime_UTR	Exon 1 of 15	NP_001398015.1	J3KPG6
	PSTPIP1	NM_001321136.2		c.-651_-648dupCCTG		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.-405_-402dupCCTG		5_prime_UTR	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559795.5	TSL:1	n.44_47dupCCTG		non_coding_transcript_exon	Exon 1 of 4
	PSTPIP1	ENST00000560223.5	TSL:1	n.-405_-402dupCCTG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000454118.1	H0YNR2

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

African (AFR) AF: 0.0351 AC: 740 AN: 21060

American (AMR) AF: 0.0511 AC: 496 AN: 9714

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 1030 AN: 9434

East Asian (EAS) AF: 0.0155 AC: 185 AN: 11946

South Asian (SAS) AF: 0.0652 AC: 3502 AN: 53682

European-Finnish (FIN) AF: 0.0894 AC: 765 AN: 8554

Middle Eastern (MID) AF: 0.102 AC: 234 AN: 2288

European-Non Finnish (NFE) AF: 0.0771 AC: 66763 AN: 865654

Other (OTH) AF: 0.0735 AC: 2671 AN: 36360

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

African (AFR) AF: 0.0392 AC: 1627 AN: 41466

American (AMR) AF: 0.0710 AC: 1083 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 373 AN: 3468

East Asian (EAS) AF: 0.0141 AC: 72 AN: 5120

South Asian (SAS) AF: 0.0658 AC: 316 AN: 4800

European-Finnish (FIN) AF: 0.104 AC: 1090 AN: 10516

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0791 AC: 5365 AN: 67854

Other (OTH) AF: 0.0784 AC: 165 AN: 2104

Alfa AF: 0.0171 Hom.: 85

Bravo AF: 0.0647

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=300/0	polymorphism (auto)

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;