chr15-76995433-C-T

Variant names:

• chr15-76995433-C-T
• rs1191640172
• NM_003978.5:c.-141C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_003978.5(PSTPIP1):​c.-141C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,374,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PSTPIP1 NM_003978.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.84
• 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: Orphanet, G2P, 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 15-76995433-C-T is Benign according to our data. Variant chr15-76995433-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3057775.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-141C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_003978.5	MANE Select	c.-141C>T		5_prime_UTR	Exon 1 of 15	NP_003969.2
	PSTPIP1	NM_001411086.1		c.-141C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001398015.1	J3KPG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.-141C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000558012.6	TSL:1 MANE Select	c.-141C>T		5_prime_UTR	Exon 1 of 15	ENSP00000452746.1	O43586-1
	PSTPIP1	ENST00000560223.5	TSL:1	n.-141C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000454118.1	H0YNR2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000674 AC: 1 AN: 148346 AF XY: 0.0000124

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000153

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1374536 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 677190

African (AFR) AF: 0.00 AC: 0 AN: 31134

American (AMR) AF: 0.00 AC: 0 AN: 31980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22712

East Asian (EAS) AF: 0.00 AC: 0 AN: 36768

South Asian (SAS) AF: 0.00 AC: 0 AN: 76924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1072250

Other (OTH) AF: 0.00 AC: 0 AN: 57118

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PSTPIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		1.8
PromoterAI		-0.065	Neutral

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: rs1191640172; hg19: chr15-77287774;