15-76995149-G-GCTGCCTGCCTGC

Variant names:

• chr15-76995149-G-GCTGCCTGCCTGC
• rs55909412
• NM_003978.5:c.-413_-402dupCCTGCCTGCCTG

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.-413_-402dupCCTGCCTGCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 151,758 control chromosomes in the GnomAD database, including 1,379 homozygotes. 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1379 hom., cov: 28)
  • Exomes 𝑓: 0.15 (10633 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSTPIP1 NM_003978.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64
• Publications: 1 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-GCTGCCTGCCTGC is Benign according to our data. Variant chr15-76995149-G-GCTGCCTGCCTGC is described in ClinVar as Benign. ClinVar VariationId is 317164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 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.-413_-402dupCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_001411086.1		c.-413_-402dupCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_001398015.1	J3KPG6
	PSTPIP1	NM_001321136.2		c.-659_-648dupCCTGCCTGCCTG		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.-413_-402dupCCTGCCTGCCTG		5_prime_UTR	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559795.5	TSL:1	n.36_47dupCCTGCCTGCCTG		non_coding_transcript_exon	Exon 1 of 4
	PSTPIP1	ENST00000560223.5	TSL:1	n.-413_-402dupCCTGCCTGCCTG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000454118.1	H0YNR2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18556 AN: 151646 Hom.: 1372 Cov.: 28

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.128

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.152 AC: 154785 AN: 1018526 Hom.: 10633 Cov.: 30 AF XY: 0.154 AC XY: 74657 AN XY: 486004

African (AFR) AF: 0.0413 AC: 870 AN: 21066

American (AMR) AF: 0.0866 AC: 841 AN: 9714

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 1614 AN: 9438

East Asian (EAS) AF: 0.0849 AC: 1013 AN: 11938

South Asian (SAS) AF: 0.212 AC: 11365 AN: 53664

European-Finnish (FIN) AF: 0.164 AC: 1403 AN: 8550

Middle Eastern (MID) AF: 0.159 AC: 363 AN: 2286

European-Non Finnish (NFE) AF: 0.152 AC: 131811 AN: 865510

Other (OTH) AF: 0.151 AC: 5505 AN: 36360

GnomAD4 genome AF: 0.122 AC: 18566 AN: 151758 Hom.: 1379 Cov.: 28 AF XY: 0.124 AC XY: 9163 AN XY: 74140

African (AFR) AF: 0.0485 AC: 2013 AN: 41464

American (AMR) AF: 0.0940 AC: 1435 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 593 AN: 3468

East Asian (EAS) AF: 0.0875 AC: 448 AN: 5122

South Asian (SAS) AF: 0.227 AC: 1089 AN: 4792

European-Finnish (FIN) AF: 0.171 AC: 1795 AN: 10514

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10811 AN: 67834

Other (OTH) AF: 0.133 AC: 279 AN: 2102

Alfa AF: 0.0606 Hom.: 85

Bravo AF: 0.109

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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; COSMIC: COSV51204908; COSMIC: COSV51204908;