rs139362350

Variant names:

• chr15-77031194-A-C
• rs139362350
• NM_003978.5:c.657A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-77031194-A-C
• chr15-77031194-A-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003978.5(PSTPIP1):​c.657A>C​(p.Gln219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000399 in 1,612,700 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q219Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.252
• Publications: 3 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009078503).
• BP6: Variant 15-77031194-A-C is Benign according to our data. Variant chr15-77031194-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 245667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 248 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.657A>C	p.Gln219His	missense	Exon 10 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.852A>C	p.Gln284His	missense	Exon 11 of 16	NP_001308066.1	O43586
	PSTPIP1	NM_001411086.1		c.657A>C	p.Gln219His	missense	Exon 10 of 15	NP_001398015.1	J3KPG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.657A>C	p.Gln219His	missense	Exon 10 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000559295.5	TSL:1	c.657A>C	p.Gln219His	missense	Exon 10 of 14	ENSP00000452743.1	O43586-2
	PSTPIP1	ENST00000559785.5	TSL:1	n.852A>C		non_coding_transcript_exon	Exon 11 of 16	ENSP00000452986.1	H0YKY3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00535

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000593 AC: 147 AN: 247912 AF XY: 0.000431

Gnomad AFR exome AF: 0.00608

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1460368 Hom.: 0 Cov.: 30 AF XY: 0.000259 AC XY: 188 AN XY: 726362

African (AFR) AF: 0.00621 AC: 208 AN: 33468

American (AMR) AF: 0.000537 AC: 24 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52528

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5760

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1111522

Other (OTH) AF: 0.000564 AC: 34 AN: 60334

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74492

African (AFR) AF: 0.00534 AC: 222 AN: 41582

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000609 Hom.: 1

Bravo AF: 0.00195

ESP6500AA AF: 0.00438 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000702 AC: 85

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (3)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.25
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.49		Loss of catalytic residue at Q219 (P = 0.2667)
MVP		0.56
MPC		0.59
ClinPred		0.058	T
GERP RS		-2.6
Varity_R		0.24
gMVP		0.64
Mutation Taster		=97/3	polymorphism

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: rs139362350; hg19: chr15-77323535;