Genetic Variant NM_003978.5:c.543G>A (chr15-77029555-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003978.5(PSTPIP1):c.543G>A(p.Lys181Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,584,092 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 9 hom. )

Consequence

PSTPIP1
NM_003978.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.47

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: 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

PSTPIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 15-77029555-G-A is Benign according to our data. Variant chr15-77029555-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.47 with no splicing effect.

BS2

High AC in GnomAd4 at 330 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	UniProt
PSTPIP1	NM_003978.5	MANE Select	c.543G>A	p.Lys181Lys	synonymous	Exon 8 of 15	NP_003969.2
PSTPIP1	NM_001321137.1		c.738G>A	p.Lys246Lys	synonymous	Exon 9 of 16	NP_001308066.1	O43586
PSTPIP1	NM_001411086.1		c.543G>A	p.Lys181Lys	synonymous	Exon 8 of 15	NP_001398015.1	J3KPG6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.543G>A	p.Lys181Lys	synonymous	Exon 8 of 15	ENSP00000452746.1	O43586-1
PSTPIP1	ENST00000559295.5	TSL:1	c.543G>A	p.Lys181Lys	synonymous	Exon 8 of 14	ENSP00000452743.1	O43586-2
PSTPIP1	ENST00000559785.5	TSL:1	n.738G>A		non_coding_transcript_exon	Exon 9 of 16	ENSP00000452986.1	H0YKY3

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00174

AC:

350

AN:

200800

AF XY:

0.00174

show subpopulations

Gnomad AFR exome

AF:

0.00466

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00291

GnomAD4 exome

AF:

0.00109

AC:

1556

AN:

1431900

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

781

AN XY:

709564

show subpopulations

African (AFR)

AF:

0.00314

AC:

103

AN:

32768

American (AMR)

AF:

0.00287

AC:

116

AN:

40376

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

320

AN:

25570

East Asian (EAS)

AF:

0.00

AC:

AN:

37960

South Asian (SAS)

AF:

0.0000612

AC:

AN:

81686

European-Finnish (FIN)

AF:

0.0000795

AC:

AN:

50312

Middle Eastern (MID)

AF:

0.00595

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000740

AC:

813

AN:

1098162

Other (OTH)

AF:

0.00271

AC:

161

AN:

59348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

170

255

340

425

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:

0.00217

AC:

330

AN:

152192

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

147

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00407

AC:

169

AN:

41512

American (AMR)

AF:

0.00262

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

67992

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00226

Hom.:

Bravo

AF:

0.00248

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (4)

Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.6

(source)

DANN

Benign

0.75

PhyloP100

2.5

Mutation Taster

=99/1

polymorphism

(source)

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

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