chr15-77031224-C-G

Variant names:

• chr15-77031224-C-G
• rs542286074
• NM_003978.5:c.687C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003978.5(PSTPIP1):​c.687C>G​(p.Asn229Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N229N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.687C>G	p.Asn229Lys	missense_variant	Exon 10 of 15	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.687C>G	p.Asn229Lys	missense_variant	Exon 10 of 15	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.0	M;.;M;.
PhyloP100		-0.22
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.79
MutPred		0.75		Gain of ubiquitination at N229 (P = 0.0258);Gain of ubiquitination at N229 (P = 0.0258);Gain of ubiquitination at N229 (P = 0.0258);.;
MVP		0.49
MPC		0.45
ClinPred		1.0	D
GERP RS		-9.2
Varity_R		0.48
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs542286074; hg19: chr15-77323565;