chr15-77029688-C-T

Variant names:

• chr15-77029688-C-T
• rs3935339
• NM_003978.5:c.562+114C>T

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.562+114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,218,290 control chromosomes in the GnomAD database, including 72,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7225 hom., cov: 32)
  • Exomes 𝑓: 0.34 (64925 hom.)
• Consequence: PSTPIP1 NM_003978.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.11
• Publications: 6 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=-0.89).
• BP6: Variant 15-77029688-C-T is Benign according to our data. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-77029688-C-T is described in CliVar as Benign. Clinvar id is 1254094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP1	NM_003978.5	c.562+114C>T		intron_variant	Intron 8 of 14	ENST00000558012.6	NP_003969.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP1	ENST00000558012.6	c.562+114C>T		intron_variant	Intron 8 of 14	1	NM_003978.5	ENSP00000452746.1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44391 AN: 151936 Hom.: 7219 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.345 AC: 367481 AN: 1066236 Hom.: 64925 AF XY: 0.344 AC XY: 182034 AN XY: 529264

African (AFR) AF: 0.154 AC: 3681 AN: 23930

American (AMR) AF: 0.312 AC: 8165 AN: 26172

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 7461 AN: 20054

East Asian (EAS) AF: 0.456 AC: 15248 AN: 33450

South Asian (SAS) AF: 0.285 AC: 18445 AN: 64606

European-Finnish (FIN) AF: 0.382 AC: 16820 AN: 44036

Middle Eastern (MID) AF: 0.305 AC: 1093 AN: 3586

European-Non Finnish (NFE) AF: 0.349 AC: 280993 AN: 804284

Other (OTH) AF: 0.338 AC: 15575 AN: 46118

GnomAD4 genome AF: 0.292 AC: 44421 AN: 152054 Hom.: 7225 Cov.: 32 AF XY: 0.294 AC XY: 21859 AN XY: 74316

African (AFR) AF: 0.159 AC: 6585 AN: 41514

American (AMR) AF: 0.295 AC: 4507 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1260 AN: 3466

East Asian (EAS) AF: 0.405 AC: 2087 AN: 5150

South Asian (SAS) AF: 0.278 AC: 1340 AN: 4824

European-Finnish (FIN) AF: 0.370 AC: 3911 AN: 10564

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23606 AN: 67934

Other (OTH) AF: 0.313 AC: 662 AN: 2114

Alfa AF: 0.321 Hom.: 1725

Bravo AF: 0.285

Asia WGS AF: 0.381 AC: 1324 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

Jan 24, 2024

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 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.82
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3935339; hg19: chr15-77322029;