dbSNP rs113386299: PSTPIP1:p.Thr68Thr (chr15-77018523-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003978.5(PSTPIP1):c.204G>A(p.Thr68Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,569,356 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 20 hom. )

Consequence

PSTPIP1
NM_003978.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.69

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 15-77018523-G-A is Benign according to our data. Variant chr15-77018523-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.69 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00828 (1260/152258) while in subpopulation AFR AF = 0.0287 (1194/41534). AF 95% confidence interval is 0.0274. There are 12 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1260 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PSTPIP1	NM_003978.5	MANE Select	c.204G>A	p.Thr68Thr	synonymous	Exon 3 of 15	NP_003969.2
PSTPIP1	NM_001321137.1		c.399G>A	p.Thr133Thr	synonymous	Exon 4 of 16	NP_001308066.1
PSTPIP1	NM_001411086.1		c.204G>A	p.Thr68Thr	synonymous	Exon 3 of 15	NP_001398015.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.204G>A	p.Thr68Thr	synonymous	Exon 3 of 15	ENSP00000452746.1
PSTPIP1	ENST00000559295.5	TSL:1	c.204G>A	p.Thr68Thr	synonymous	Exon 3 of 14	ENSP00000452743.1
PSTPIP1	ENST00000559785.5	TSL:1	n.399G>A		non_coding_transcript_exon	Exon 4 of 16	ENSP00000452986.1

Frequencies

GnomAD3 genomes

AF:

0.00826

AC:

1257

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00194

AC:

345

AN:

177612

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000426

GnomAD4 exome

AF:

0.000886

AC:

1256

AN:

1417098

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

517

AN XY:

700732

show subpopulations

African (AFR)

AF:

0.0302

AC:

984

AN:

32606

American (AMR)

AF:

0.00151

AC:

AN:

37734

Ashkenazi Jewish (ASJ)

AF:

0.000198

AC:

AN:

25290

East Asian (EAS)

AF:

0.0000532

AC:

AN:

37568

South Asian (SAS)

AF:

0.0000870

AC:

AN:

80470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49918

Middle Eastern (MID)

AF:

0.000540

AC:

AN:

5560

European-Non Finnish (NFE)

AF:

0.0000606

AC:

AN:

1089234

Other (OTH)

AF:

0.00225

AC:

132

AN:

58718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00828

AC:

1260

AN:

152258

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

615

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0287

AC:

1194

AN:

41534

American (AMR)

AF:

0.00288

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68024

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00373

Hom.:

Bravo

AF:

0.00901

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (4)

Autoinflammatory syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.0

(source)

DANN

Benign

0.89

PhyloP100

-1.7

PromoterAI

-0.040

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over