rs1553920379

Positions:

• chr4-101032294-A-AAAGT

Variant summary

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

The NM_000944.5(PPP3CA):​c.1311_1312insACTT​(p.Ser438ThrfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L437L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA NM_000944.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.610

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 4-101032294-A-AAAGT is Pathogenic according to our data. Variant chr4-101032294-A-AAAGT is described in ClinVar as [Pathogenic]. Clinvar id is 522802.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.1311_1312insACTT	p.Ser438ThrfsTer14	frameshift_variant	12/14	ENST00000394854.8
PPP3CA	NM_001130691.2	c.1311_1312insACTT	p.Ser438ThrfsTer20	frameshift_variant	12/13
PPP3CA	NM_001130692.2	c.1185_1186insACTT	p.Ser396ThrfsTer20	frameshift_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1311_1312insACTT	p.Ser438ThrfsTer14	frameshift_variant	12/14	1	NM_000944.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Nov 26, 2017

This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID: 18414213) and was found de novo in a 10-year-old male with epilepsy, developmental regression, global developmental delay, autism spectrum disorder, poor coordination, hyperreflexia with clonus, hypotonia, high pain threshold, high resting body temperature, and GI constipation and reflux. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553920379; hg19: chr4-101953451;