rs34908107

chr15-77035928-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003978.5(PSTPIP1):c.1112C>T(p.Thr371Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,602,112 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: PSTPIP1 NM_003978.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0150

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009748578).
• BP6: Variant 15-77035928-C-T is Benign according to our data. Variant chr15-77035928-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 317185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77035928-C-T is described in Lovd as [Benign]. Variant chr15-77035928-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 494 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSTPIP1	NM_003978.5	c.1112C>T	p.Thr371Ile	missense_variant	14/15	ENST00000558012.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.1112C>T	p.Thr371Ile	missense_variant	14/15	1	NM_003978.5	P3

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000873 AC: 201 AN: 230320 Hom.: 2 AF XY: 0.000653 AC XY: 82 AN XY: 125600

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000693

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000773

Gnomad OTH exome AF: 0.000530

GnomAD4 exome AF: 0.000391 AC: 567 AN: 1449856 Hom.: 2 Cov.: 34 AF XY: 0.000325 AC XY: 234 AN XY: 720516

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.000714

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000472

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000397

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00331 AC XY: 246 AN XY: 74432

Gnomad4 AFR AF: 0.0112

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000960 Hom.: 0

Bravo AF: 0.00380

ESP6500AA AF: 0.00904 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000994 AC: 119

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyogenic arthritis-pyoderma gangrenosum-acne syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 13, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.7
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.072	N
LIST_S2	Uncertain	0.87	D;D;D
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;N
Sift	Benign	0.070	T;T;T
Sift4G	Benign	0.075	T;T;T
Polyphen		0.29	B;.;B
Vest4		0.32
MVP		0.52
MPC		0.17
ClinPred		0.0011	T
GERP RS		0.27
Varity_R		0.041
gMVP		0.35

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

Other links and lift over

dbSNP: rs34908107; hg19: chr15-77328269;