4-101025887-C-T

Variant names:

• chr4-101025887-C-T
• NM_000944.5:c.1544G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Moderate BP6_Moderate

The NM_000944.5(PPP3CA):​c.1544G>A​(p.Ser515Asn) 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.27

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 -1 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=0.14734504).
• BP6: Variant 4-101025887-C-T is Benign according to our data. Variant chr4-101025887-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1343178.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1544G>A	p.Ser515Asn	missense_variant	Exon 14 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1514G>A	p.Ser505Asn	missense_variant	Exon 13 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1388G>A	p.Ser463Asn	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.1544G>A	p.Ser515Asn	missense_variant	Exon 14 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental disorder Benign:1

Mar 04, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;T;.;.;.
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.070	N;N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.23, 0.34	.;B;.;B;B
Vest4		0.24
MutPred		0.090		.;Loss of phosphorylation at S515 (P = 0.0283);.;.;.;
MVP		0.37
MPC		1.0
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.17
gMVP		0.64

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: chr4-101947044;