4-101083203-G-C

Position:

• chr4-101083203-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000394854.8(PPP3CA):​c.843C>G​(p.His281Gln) variant causes a missense change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. H281H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CA ENST00000394854.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.767

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 11 ACMG points.

• PM1: In a region_of_interest Catalytic (size 284) in uniprot entity PP2BA_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in ENST00000394854.8
• 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). GenCC has associacion of 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, 0.99
• PP5: Variant 4-101083203-G-C is Pathogenic according to our data. Variant chr4-101083203-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 441274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.843C>G	p.His281Gln	missense_variant	7/14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.843C>G	p.His281Gln	missense_variant	7/13		NP_001124163.1
PPP3CA	NM_001130692.2	c.843C>G	p.His281Gln	missense_variant	7/12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.843C>G	p.His281Gln	missense_variant	7/14	1	NM_000944.5	ENSP00000378323	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy 91 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 03, 2023	PS4_Supporting, PM1, PM2, PM6, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.95
MutPred		0.89		Loss of catalytic residue at R279 (P = 0.1053);Loss of catalytic residue at R279 (P = 0.1053);Loss of catalytic residue at R279 (P = 0.1053);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		-1.6
Varity_R		0.96
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs199706529; hg19: chr4-102004360;