rs200771233

Variant names:

• chr15-77037076-A-C
• rs200771233
• NM_003978.5:c.1151A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-77037076-A-C
• chr15-77037076-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003978.5(PSTPIP1):​c.1151A>C​(p.Asp384Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D384G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.37
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.1151A>C	p.Asp384Ala	missense	Exon 15 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1346A>C	p.Asp449Ala	missense	Exon 16 of 16	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.1142A>C	p.Asp381Ala	missense	Exon 15 of 15	NP_001398015.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.1151A>C	p.Asp384Ala	missense	Exon 15 of 15	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.1094A>C	p.Asp365Ala	missense	Exon 14 of 14	ENSP00000452743.1
	PSTPIP1	ENST00000558870.1	TSL:1	c.299A>C	p.Asp100Ala	missense	Exon 4 of 4	ENSP00000452779.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460026 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726276

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		8.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		0.90	P
Vest4		0.82
MutPred		0.89		Gain of sheet (P = 0.0827)
MVP		0.85
MPC		0.70
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.31
gMVP		0.82
Mutation Taster		=68/32	polymorphism

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: rs200771233; hg19: chr15-77329417;