NM_003978.5:c.212+1169G>A

Variant names:

• chr15-77019700-G-A
• rs16968623
• NM_003978.5:c.212+1169G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003978.5(PSTPIP1):​c.212+1169G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 152,122 control chromosomes in the GnomAD database, including 28,249 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (28249 hom., cov: 33)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.737
• Publications: 6 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: G2P, Orphanet, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.212+1169G>A		intron_variant	Intron 3 of 14	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.212+1169G>A		intron_variant	Intron 3 of 14	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88062 AN: 152004 Hom.: 28251 Cov.: 33

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.847

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.615

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.579 AC: 88074 AN: 152122 Hom.: 28249 Cov.: 33 AF XY: 0.574 AC XY: 42655 AN XY: 74348

African (AFR) AF: 0.300 AC: 12442 AN: 41490

American (AMR) AF: 0.539 AC: 8237 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2547 AN: 3472

East Asian (EAS) AF: 0.481 AC: 2479 AN: 5156

South Asian (SAS) AF: 0.646 AC: 3116 AN: 4824

European-Finnish (FIN) AF: 0.670 AC: 7091 AN: 10586

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.733 AC: 49873 AN: 67994

Other (OTH) AF: 0.615 AC: 1301 AN: 2114

Alfa AF: 0.690 Hom.: 16600

Bravo AF: 0.557

Asia WGS AF: 0.567 AC: 1973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.67
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs16968623; hg19: chr15-77312041;