rs1553920383

Positions:

• chr4-101032349-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000944.5(PPP3CA):​c.1255_1256del​(p.Ser419CysfsTer31) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP3CA NM_000944.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.73

Genes affected

PPP3CA (HGNC:9314): (protein phosphatase 3 catalytic subunit alpha) Enables several functions, including ATPase binding activity; calmodulin binding activity; and calmodulin-dependent protein phosphatase activity. Involved in several processes, including calcineurin-NFAT signaling cascade; peptidyl-serine dephosphorylation; and response to calcium ion. Located in several cellular components, including cytosol; dendritic spine; and nucleoplasm. Part of calcineurin complex. Colocalizes with cytoplasmic side of plasma membrane. Implicated in developmental and epileptic encephalopathy 91. Biomarker of focal segmental glomerulosclerosis and schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-101032349-ACT-A is Pathogenic according to our data. Variant chr4-101032349-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 496636.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP3CA	NM_000944.5	c.1255_1256del	p.Ser419CysfsTer31	frameshift_variant	12/14	ENST00000394854.8
PPP3CA	NM_001130691.2	c.1255_1256del	p.Ser419CysfsTer37	frameshift_variant	12/13
PPP3CA	NM_001130692.2	c.1129_1130del	p.Ser377CysfsTer37	frameshift_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1255_1256del	p.Ser419CysfsTer31	frameshift_variant	12/14	1	NM_000944.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy, infantile or early childhood, 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center for Molecular Medicine, Children’s Hospital of Fudan University

Feb 11, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2023

Frameshift variant predicted to result in protein truncation, as the last 103 amino acids are replaced with 30 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30455226) -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553920383; hg19: chr4-101953506;