rs201582038

Variant names:

• chr15-77035518-C-T
• rs201582038
• NM_003978.5:c.940C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003978.5(PSTPIP1):​c.940C>T​(p.Leu314Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,591,938 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (6 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.12
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-77035518-C-T is Benign according to our data. Variant chr15-77035518-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000498 (717/1439656) while in subpopulation AFR AF = 0.0166 (545/32904). AF 95% confidence interval is 0.0154. There are 6 homozygotes in GnomAdExome4. There are 313 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 682 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003978.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.940C>T	p.Leu314Leu	synonymous	Exon 13 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1135C>T	p.Leu379Leu	synonymous	Exon 14 of 16	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.940C>T	p.Leu314Leu	synonymous	Exon 13 of 15	NP_001398015.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.940C>T	p.Leu314Leu	synonymous	Exon 13 of 15	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.883C>T	p.Leu295Leu	synonymous	Exon 12 of 14	ENSP00000452743.1
	PSTPIP1	ENST00000558870.1	TSL:1	c.88C>T	p.Leu30Leu	synonymous	Exon 2 of 4	ENSP00000452779.1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 681 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000945 AC: 204 AN: 215976 AF XY: 0.000692

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000484

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000153

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000183

GnomAD4 exome AF: 0.000498 AC: 717 AN: 1439656 Hom.: 6 Cov.: 31 AF XY: 0.000438 AC XY: 313 AN XY: 714254

African (AFR) AF: 0.0166 AC: 545 AN: 32904

American (AMR) AF: 0.000552 AC: 23 AN: 41702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 38634

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82976

European-Finnish (FIN) AF: 0.000276 AC: 14 AN: 50672

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000762 AC: 84 AN: 1101646

Other (OTH) AF: 0.000821 AC: 49 AN: 59662

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74464

African (AFR) AF: 0.0155 AC: 646 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00246 Hom.: 0

Bravo AF: 0.00527

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (3)
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.7
DANN	Benign	0.86
PhyloP100		1.1
Mutation Taster		=99/1	polymorphism

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: rs201582038; hg19: chr15-77327859;