4-101025893-T-C

Variant names:

• chr4-101025893-T-C
• rs199874915
• NM_000944.5:c.1538A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000944.5(PPP3CA):​c.1538A>G​(p.Asn513Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,591,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.57

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 -6 ACMG points.

• 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=0.11734682).
• BP6: Variant 4-101025893-T-C is Benign according to our data. Variant chr4-101025893-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1474325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1538A>G	p.Asn513Ser	missense_variant	Exon 14 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1508A>G	p.Asn503Ser	missense_variant	Exon 13 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1382A>G	p.Asn461Ser	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.1538A>G	p.Asn513Ser	missense_variant	Exon 14 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 149808 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000327 AC: 8 AN: 244530 Hom.: 0 AF XY: 0.0000302 AC XY: 4 AN XY: 132366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000725

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1442020 Hom.: 0 Cov.: 35 AF XY: 0.0000223 AC XY: 16 AN XY: 717126

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: 0.0000227

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 149808 Hom.: 0 Cov.: 30 AF XY: 0.0000137 AC XY: 1 AN XY: 72988

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy 91;C4748872:Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development Uncertain:1

Apr 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 513 of the PPP3CA protein (p.Asn513Ser). This variant is present in population databases (rs199874915, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PPP3CA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1474325). 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. -

Inborn genetic diseases Benign:1

Aug 26, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.66	N;N;N;N;N
REVEL	Benign	0.045
Sift	Uncertain	0.012	D;D;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0090, 0.015, 0.0030	.;B;.;B;B
Vest4		0.25
MutPred		0.13		.;Gain of glycosylation at N513 (P = 0.0075);.;.;.;
MVP		0.53
MPC		0.87
ClinPred		0.12	T
GERP RS		6.0
Varity_R		0.098
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs199874915; hg19: chr4-101947050;