15-77032329-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003978.5(PSTPIP1):​c.773G>C​(p.Gly258Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,612,608 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 26 hom., cov: 33)
Exomes 𝑓: 0.0037 ( 55 hom. )

Consequence

PSTPIP1
NM_003978.5 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.94
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007782966).
BP6
Variant 15-77032329-G-C is Benign according to our data. Variant chr15-77032329-G-C is described in ClinVar as [Benign]. Clinvar id is 259211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77032329-G-C is described in Lovd as [Benign]. Variant chr15-77032329-G-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1988/152376) while in subpopulation AFR AF= 0.0358 (1489/41584). AF 95% confidence interval is 0.0343. There are 26 homozygotes in gnomad4. There are 915 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1988 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PSTPIP1NM_003978.5 linkc.773G>C p.Gly258Ala missense_variant Exon 11 of 15 ENST00000558012.6 NP_003969.2 O43586-1A0A0S2Z5P3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PSTPIP1ENST00000558012.6 linkc.773G>C p.Gly258Ala missense_variant Exon 11 of 15 1 NM_003978.5 ENSP00000452746.1 O43586-1

Frequencies

GnomAD3 genomes
AF:
0.0130
AC:
1985
AN:
152258
Hom.:
26
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0358
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00870
Gnomad ASJ
AF:
0.0276
Gnomad EAS
AF:
0.0192
Gnomad SAS
AF:
0.00227
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.00176
Gnomad OTH
AF:
0.0153
GnomAD3 exomes
AF:
0.00820
AC:
2028
AN:
247418
Hom.:
26
AF XY:
0.00712
AC XY:
961
AN XY:
134942
show subpopulations
Gnomad AFR exome
AF:
0.0325
Gnomad AMR exome
AF:
0.0152
Gnomad ASJ exome
AF:
0.0279
Gnomad EAS exome
AF:
0.0198
Gnomad SAS exome
AF:
0.00281
Gnomad FIN exome
AF:
0.000186
Gnomad NFE exome
AF:
0.00203
Gnomad OTH exome
AF:
0.00948
GnomAD4 exome
AF:
0.00368
AC:
5377
AN:
1460232
Hom.:
55
Cov.:
31
AF XY:
0.00348
AC XY:
2527
AN XY:
726400
show subpopulations
Gnomad4 AFR exome
AF:
0.0378
Gnomad4 AMR exome
AF:
0.0144
Gnomad4 ASJ exome
AF:
0.0268
Gnomad4 EAS exome
AF:
0.0128
Gnomad4 SAS exome
AF:
0.00276
Gnomad4 FIN exome
AF:
0.000172
Gnomad4 NFE exome
AF:
0.00131
Gnomad4 OTH exome
AF:
0.00743
GnomAD4 genome
AF:
0.0130
AC:
1988
AN:
152376
Hom.:
26
Cov.:
33
AF XY:
0.0123
AC XY:
915
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.0358
Gnomad4 AMR
AF:
0.00862
Gnomad4 ASJ
AF:
0.0276
Gnomad4 EAS
AF:
0.0193
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00176
Gnomad4 OTH
AF:
0.0151
Alfa
AF:
0.00461
Hom.:
2
Bravo
AF:
0.0154
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.0272
AC:
114
ESP6500EA
AF:
0.00297
AC:
25
ExAC
AF:
0.00772
AC:
932
Asia WGS
AF:
0.0100
AC:
36
AN:
3478
EpiCase
AF:
0.00322
EpiControl
AF:
0.00314

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 21790734, 24233262, 23426477) -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PSTPIP1: BP4, BS1, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3
Sep 27, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autoinflammatory syndrome Benign:1
Feb 18, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
16
DANN
Benign
0.66
DEOGEN2
Benign
0.14
T;.;.;T
Eigen
Benign
-0.013
Eigen_PC
Benign
0.057
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.13
T;T;T;T
MetaRNN
Benign
0.0078
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M;.;M;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.2
N;N;N;N
REVEL
Benign
0.086
Sift
Benign
0.76
T;T;T;T
Sift4G
Benign
0.76
T;T;T;T
Polyphen
0.49
P;.;P;.
Vest4
0.45
MVP
0.68
MPC
0.16
ClinPred
0.018
T
GERP RS
5.0
Varity_R
0.055
gMVP
0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34240327; hg19: chr15-77324670; COSMIC: COSV99059046; COSMIC: COSV99059046; API