4-101025888-T-A

Variant names:

• chr4-101025888-T-A
• NM_000944.5:c.1543A>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_000944.5(PPP3CA):​c.1543A>T​(p.Ser515Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,396,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PPP3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.6261 (above the threshold of 3.09). Trascript score misZ: 4.4954 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.20994976).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1543A>T	p.Ser515Cys	missense_variant	Exon 14 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1513A>T	p.Ser505Cys	missense_variant	Exon 13 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1387A>T	p.Ser463Cys	missense_variant	Exon 12 of 12		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.1543A>T	p.Ser515Cys	missense_variant	Exon 14 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1396090 Hom.: 0 Cov.: 35 AF XY: 0.00000144 AC XY: 1 AN XY: 694444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000467

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 515 of the PPP3CA protein (p.Ser515Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPP3CA-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.32	.;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	.;N;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		0.94, 0.96	.;P;.;D;P
Vest4		0.39
MutPred		0.093		.;Loss of phosphorylation at S515 (P = 0.0283);.;.;.;
MVP		0.37
MPC		1.1
ClinPred		0.85	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.73

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: chr4-101947045;