4-101083202-C-T

Position:

• chr4-101083202-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000944.5(PPP3CA):​c.844G>A​(p.Glu282Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.38

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP3CA. . Gene score misZ: 3.6261 (greater than the threshold 3.09). Trascript score misZ: 4.4954 (greater than threshold 3.09). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. GenCC has associacion of the gene with epileptic encephalopathy, infantile or early childhood, 1, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 4-101083202-C-T is Pathogenic according to our data. Variant chr4-101083202-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 441275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.844G>A	p.Glu282Lys	missense_variant	7/14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.844G>A	p.Glu282Lys	missense_variant	7/13		NP_001124163.1
PPP3CA	NM_001130692.2	c.844G>A	p.Glu282Lys	missense_variant	7/12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.844G>A	p.Glu282Lys	missense_variant	7/14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy 91 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 29, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 91 (MIM#617711), and arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development (MIM#618265), respectively (PMIDs: 32593294, 29432562). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated protein phosphatase 2B (PP2B) catalytic domain (PMID: 28942967). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo in multiple affected individuals (PMIDs: 28942967, 33963760). (SP) 1010 - Functional evidence for this variant is inconclusive. Overexpression studies using yeast showed the mutant maintained tolerance to growth condition with high extracellular Ca2+, similar to wild-type (PMID: 29432562). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11461966, 20700442, 10473536, 25262651, 27597899, 8052858, 15800199, 25245802, 3029762, 24140049, 22015374, 10627609, 28942967, 33963760) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 282 of the PPP3CA protein (p.Glu282Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PPP3CA-related conditions (PMID: 28942967). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 441275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPP3CA protein function. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2016

- -

Developmental and epileptic encephalopathy 91;C4748872:Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Lab, CHRU Brest

-

- -

Epileptic encephalopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	4.0	H;H;H;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.90
MutPred		0.70		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);.;
MVP		0.78
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553923787; hg19: chr4-102004359; COSMIC: COSV59920640;