NM_003978.5:c.1143C>T

Variant names:

• chr15-77037068-C-T
• rs141227274
• NM_003978.5:c.1143C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003978.5(PSTPIP1):​c.1143C>T​(p.Ser381Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,236 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: PSTPIP1 NM_003978.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.68
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-77037068-C-T is Benign according to our data. Variant chr15-77037068-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.68 with no splicing effect.
• BS2: High AC in GnomAd4 at 246 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	NM_003978.5	MANE Select	c.1143C>T	p.Ser381Ser	synonymous	Exon 15 of 15	NP_003969.2
	PSTPIP1	NM_001321137.1		c.1338C>T	p.Ser446Ser	synonymous	Exon 16 of 16	NP_001308066.1
	PSTPIP1	NM_001411086.1		c.1134C>T	p.Ser378Ser	synonymous	Exon 15 of 15	NP_001398015.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.1143C>T	p.Ser381Ser	synonymous	Exon 15 of 15	ENSP00000452746.1
	PSTPIP1	ENST00000559295.5	TSL:1	c.1086C>T	p.Ser362Ser	synonymous	Exon 14 of 14	ENSP00000452743.1
	PSTPIP1	ENST00000558870.1	TSL:1	c.291C>T	p.Ser97Ser	synonymous	Exon 4 of 4	ENSP00000452779.1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00139 AC: 343 AN: 246630 AF XY: 0.00141

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00457

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.00135 AC: 1973 AN: 1459972 Hom.: 4 Cov.: 31 AF XY: 0.00141 AC XY: 1026 AN XY: 726254

African (AFR) AF: 0.000717 AC: 24 AN: 33476

American (AMR) AF: 0.000246 AC: 11 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26114

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39690

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86254

European-Finnish (FIN) AF: 0.00456 AC: 237 AN: 52016

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00141 AC: 1562 AN: 1111620

Other (OTH) AF: 0.000779 AC: 47 AN: 60332

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74450

African (AFR) AF: 0.000481 AC: 20 AN: 41542

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Pyogenic arthritis-pyoderma gangrenosum-acne syndrome (3)
-	-	1	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.89
DANN	Benign	0.78
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs141227274; hg19: chr15-77329409; COSMIC: COSV108036226;