chr4-101083202-C-G

Variant names:

• chr4-101083202-C-G
• rs1553923787
• NM_000944.5:c.844G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000944.5(PPP3CA):​c.844G>C​(p.Glu282Gln) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E282K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

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]

PPP3CA Gene-Disease associations (from GenCC):

• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• developmental and epileptic encephalopathy 91

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000944.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-101083202-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 441275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.844G>C	p.Glu282Gln	missense_variant	Exon 7 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.844G>C	p.Glu282Gln	missense_variant	Exon 7 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.844G>C	p.Glu282Gln	missense_variant	Exon 7 of 12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.844G>C	p.Glu282Gln	missense_variant	Exon 7 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Glu282 amino acid residue in PPP3CA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28942967). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with PPP3CA-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 282 of the PPP3CA protein (p.Glu282Gln). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L;L;.
PhyloP100		7.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.99	D;.;D;D
Vest4		0.86
MutPred		0.63		Gain of MoRF binding (P = 0.0728);Gain of MoRF binding (P = 0.0728);Gain of MoRF binding (P = 0.0728);.;
MVP		0.72
MPC		2.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.84
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553923787; hg19: chr4-102004359;