chr4-101025872-A-C

Position:

• chr4-101025872-A-C

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.1559T>G​(p.Ile520Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I520M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

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=0.22076803).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP3CA	NM_000944.5	c.1559T>G	p.Ile520Ser	missense_variant	14/14	ENST00000394854.8
PPP3CA	NM_001130691.2	c.1529T>G	p.Ile510Ser	missense_variant	13/13
PPP3CA	NM_001130692.2	c.1403T>G	p.Ile468Ser	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1559T>G	p.Ile520Ser	missense_variant	14/14	1	NM_000944.5	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 520 of the PPP3CA protein (p.Ile520Ser). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1356943). This variant has not been reported in the literature in individuals affected with PPP3CA-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.16	.;T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0036
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.43	N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.017, 0.029, 0.0070	.;B;.;B;B
Vest4		0.53
MutPred		0.13		.;Gain of phosphorylation at I520 (P = 0.0079);.;.;.;
MVP		0.69
MPC		1.5
ClinPred		0.64	D
GERP RS		4.8
Varity_R		0.22
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr4-101947029;