Genetic Variant PSTPIP1:n.26+155C>T (chr15-76994970-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001321137.1(PSTPIP1):c.26+155C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,200,650 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 8 hom. )

Consequence

PSTPIP1
NM_001321137.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.76

Publications

0 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:

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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=-0.88).

BP6

Variant 15-76994970-C-T is Benign according to our data. Variant chr15-76994970-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1218031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00744 (1132/152228) while in subpopulation AFR AF = 0.025 (1040/41524). AF 95% confidence interval is 0.0238. There are 8 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1132 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321137.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSTPIP1	NM_001321137.1		c.26+155C>T	intron	N/A	NP_001308066.1	O43586
PSTPIP1	NM_003978.5	MANE Select	c.-604C>T	upstream_gene	N/A	NP_003969.2
PSTPIP1	NM_001411086.1		c.-604C>T	upstream_gene	N/A	NP_001398015.1	J3KPG6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PSTPIP1	ENST00000559785.5	TSL:1	n.26+155C>T	intron	N/A	ENSP00000452986.1	H0YKY3
PSTPIP1	ENST00000884367.1		c.-167+155C>T	intron	N/A	ENSP00000554426.1
PSTPIP1	ENST00000558407.5	TSL:3	c.26+155C>T	intron	N/A	ENSP00000453268.1	H0YLM9

Frequencies

GnomAD3 genomes

AF:

0.00741

AC:

1127

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0250

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00669

GnomAD4 exome

AF:

0.000736

AC:

772

AN:

1048422

Hom.:

Cov.:

AF XY:

0.000670

AC XY:

343

AN XY:

511994

show subpopulations

African (AFR)

AF:

0.0255

AC:

561

AN:

21990

American (AMR)

AF:

0.00260

AC:

AN:

20754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11822

East Asian (EAS)

AF:

0.00

AC:

AN:

12316

South Asian (SAS)

AF:

0.0000593

AC:

AN:

67474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.00304

AC:

AN:

3624

European-Non Finnish (NFE)

AF:

0.0000974

AC:

AN:

862048

Other (OTH)

AF:

0.00153

AC:

AN:

37882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00744

AC:

1132

AN:

152228

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

557

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0250

AC:

1040

AN:

41524

American (AMR)

AF:

0.00431

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67998

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

116

175

233

291

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:

0.00519

Hom.:

Bravo

AF:

0.00859

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.12

(source)

DANN

Benign

0.35

PhyloP100

-2.8

PromoterAI

0.031

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over