15-76995149-GCTGCCTGCCTGC-GCTGCCTGCCTGCCTGCCTGC

Variant names:

• chr15-76995149-G-GCTGCCTGC
• rs55909412
• NM_003978.5:c.-409_-402dupCCTGCCTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003978.5(PSTPIP1):​c.-409_-402dupCCTGCCTG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 151,812 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00036 (1 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 61 Unknown,AD gene.

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.-409_-402dupCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_001411086.1		c.-409_-402dupCCTGCCTG		5_prime_UTR	Exon 1 of 15	NP_001398015.1	J3KPG6
	PSTPIP1	NM_001321136.2		c.-655_-648dupCCTGCCTG		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.-409_-402dupCCTGCCTG		5_prime_UTR	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559795.5	TSL:1	n.40_47dupCCTGCCTG		non_coding_transcript_exon	Exon 1 of 4
	PSTPIP1	ENST00000560223.5	TSL:1	n.-409_-402dupCCTGCCTG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000454118.1	H0YNR2

Frequencies

GnomAD3 genomes AF: 0.000402 AC: 61 AN: 151700 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00175

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.000480

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000363 AC: 369 AN: 1015606 Hom.: 1 Cov.: 30 AF XY: 0.000363 AC XY: 176 AN XY: 484542

African (AFR) AF: 0.000190 AC: 4 AN: 21060

American (AMR) AF: 0.000412 AC: 4 AN: 9704

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 27 AN: 9418

East Asian (EAS) AF: 0.00335 AC: 40 AN: 11942

South Asian (SAS) AF: 0.000827 AC: 44 AN: 53236

European-Finnish (FIN) AF: 0.000352 AC: 3 AN: 8532

Middle Eastern (MID) AF: 0.000879 AC: 2 AN: 2276

European-Non Finnish (NFE) AF: 0.000261 AC: 225 AN: 863200

Other (OTH) AF: 0.000552 AC: 20 AN: 36238

GnomAD4 genome AF: 0.000402 AC: 61 AN: 151812 Hom.: 0 Cov.: 28 AF XY: 0.000391 AC XY: 29 AN XY: 74178

African (AFR) AF: 0.000265 AC: 11 AN: 41470

American (AMR) AF: 0.000197 AC: 3 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00176 AC: 9 AN: 5122

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4800

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67856

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000140 Hom.: 85

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;