NM_003978.5:c.36+68G>A

Variant names:

• chr15-76995677-G-A
• rs2254441
• NM_003978.5:c.36+68G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003978.5(PSTPIP1):​c.36+68G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,609,522 control chromosomes in the GnomAD database, including 50,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7798 hom., cov: 33)
  • Exomes 𝑓: 0.23 (42801 hom.)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.77
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-76995677-G-A is Benign according to our data. Variant chr15-76995677-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.36+68G>A		intron_variant	Intron 1 of 14	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.36+68G>A		intron_variant	Intron 1 of 14	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45100 AN: 152072 Hom.: 7777 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.229 AC: 333063 AN: 1457332 Hom.: 42801 AF XY: 0.227 AC XY: 164704 AN XY: 725124

African (AFR) AF: 0.442 AC: 14752 AN: 33338

American (AMR) AF: 0.452 AC: 20181 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4156 AN: 26108

East Asian (EAS) AF: 0.488 AC: 19372 AN: 39672

South Asian (SAS) AF: 0.290 AC: 24945 AN: 86108

European-Finnish (FIN) AF: 0.214 AC: 11412 AN: 53284

Middle Eastern (MID) AF: 0.154 AC: 660 AN: 4298

European-Non Finnish (NFE) AF: 0.201 AC: 223257 AN: 1109806

Other (OTH) AF: 0.238 AC: 14328 AN: 60102

GnomAD4 genome AF: 0.297 AC: 45149 AN: 152190 Hom.: 7798 Cov.: 33 AF XY: 0.302 AC XY: 22474 AN XY: 74416

African (AFR) AF: 0.435 AC: 18074 AN: 41506

American (AMR) AF: 0.372 AC: 5689 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 584 AN: 3472

East Asian (EAS) AF: 0.519 AC: 2684 AN: 5170

South Asian (SAS) AF: 0.323 AC: 1561 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2337 AN: 10598

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13510 AN: 68002

Other (OTH) AF: 0.267 AC: 563 AN: 2108

Alfa AF: 0.258 Hom.: 981

Bravo AF: 0.313

Asia WGS AF: 0.411 AC: 1426 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.42
PhyloP100		-1.8
PromoterAI		0.053	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2254441; hg19: chr15-77288018;