chr4-101025918-A-G

Position:

• chr4-101025918-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000944.5(PPP3CA):​c.1513T>C​(p.Ser505Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 1 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). 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12767705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1513T>C	p.Ser505Pro	missense_variant	14/14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1483T>C	p.Ser495Pro	missense_variant	13/13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1357T>C	p.Ser453Pro	missense_variant	12/12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1513T>C	p.Ser505Pro	missense_variant	14/14	1	NM_000944.5	ENSP00000378323	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The observed missense c.1513T>C (p.Ser505Pro) variant in PPP3CA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser505Pro variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. The amino acid change p.Ser505Pro in PPP3CA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 505 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	.;T;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.67	N;N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.059	T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.0	.;B;.;B;B
Vest4		0.12
MutPred		0.092		.;Loss of helix (P = 0.0123);.;.;.;
MVP		0.42
MPC		1.3
ClinPred		0.77	D
GERP RS		6.1
Varity_R		0.15
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-101947075;