15-77032539-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003978.5(PSTPIP1):c.838+145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 825,384 control chromosomes in the GnomAD database, including 167,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 27462 hom., cov: 33)

Exomes 𝑓: 0.64 ( 140080 hom. )

Consequence

PSTPIP1
NM_003978.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.894

Publications

17 publications found

Variant links:

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

PSTPIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 15-77032539-A-G is Benign according to our data. Variant chr15-77032539-A-G is described in ClinVar as Benign. ClinVar VariationId is 440205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5 link	c.838+145A>G		intron_variant	Intron 11 of 14	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6 link	c.838+145A>G		intron_variant	Intron 11 of 14	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes

AF:

0.595

AC:

90411

AN:

151946

Hom.:

27437

Cov.:

show subpopulations

Gnomad AFR

AF:

0.493

Gnomad AMI

AF:

0.758

Gnomad AMR

AF:

0.541

Gnomad ASJ

AF:

0.696

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.631

Gnomad MID

AF:

0.729

Gnomad NFE

AF:

0.666

Gnomad OTH

AF:

0.612

GnomAD2 exomes

AF:

0.603

AC:

49589

AN:

82188

AF XY:

0.610

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.533

Gnomad ASJ exome

AF:

0.696

Gnomad EAS exome

AF:

0.470

Gnomad FIN exome

AF:

0.658

Gnomad NFE exome

AF:

0.671

Gnomad OTH exome

AF:

0.635

GnomAD4 exome

AF:

0.641

AC:

431466

AN:

673320

Hom.:

140080

Cov.:

AF XY:

0.640

AC XY:

220453

AN XY:

344558

show subpopulations

African (AFR)

AF:

0.488

AC:

8188

AN:

16776

American (AMR)

AF:

0.523

AC:

11888

AN:

22732

Ashkenazi Jewish (ASJ)

AF:

0.693

AC:

11085

AN:

16004

East Asian (EAS)

AF:

0.528

AC:

16963

AN:

32102

South Asian (SAS)

AF:

0.591

AC:

31338

AN:

53018

European-Finnish (FIN)

AF:

0.652

AC:

22900

AN:

35112

Middle Eastern (MID)

AF:

0.736

AC:

3035

AN:

4122

European-Non Finnish (NFE)

AF:

0.662

AC:

304677

AN:

459916

Other (OTH)

AF:

0.638

AC:

21392

AN:

33538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

7840

15681

23521

31362

39202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5050

10100

15150

20200

25250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.595

AC:

90481

AN:

152064

Hom.:

27462

Cov.:

AF XY:

0.590

AC XY:

43840

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.494

AC:

20474

AN:

41456

American (AMR)

AF:

0.540

AC:

8261

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.696

AC:

2415

AN:

3472

East Asian (EAS)

AF:

0.482

AC:

2486

AN:

5158

South Asian (SAS)

AF:

0.561

AC:

2703

AN:

4820

European-Finnish (FIN)

AF:

0.631

AC:

6678

AN:

10576

Middle Eastern (MID)

AF:

0.726

AC:

212

AN:

292

European-Non Finnish (NFE)

AF:

0.666

AC:

45270

AN:

67978

Other (OTH)

AF:

0.612

AC:

1291

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1911

3821

5732

7642

9553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.641

Hom.:

76902

Bravo

AF:

0.585

Asia WGS

AF:

0.574

AC:

1996

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported.

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome

Benign:1

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.9

(source)

DANN

Benign

0.63

PhyloP100

0.89

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over