chr4-101025868-C-A

Variant names:

• chr4-101025868-C-A
• NM_000944.5:c.1563G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000944.5(PPP3CA):​c.1563G>T​(p.Gln521His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CA NM_000944.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.45

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 2 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=0.39055654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.1563G>T	p.Gln521His	missense_variant	Exon 14 of 14	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.1533G>T	p.Gln511His	missense_variant	Exon 13 of 13		NP_001124163.1
PPP3CA	NM_001130692.2	c.1407G>T	p.Gln469His	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.1563G>T	p.Gln521His	missense_variant	Exon 14 of 14	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000106 AC: 1 AN: 947712 Hom.: 0 Cov.: 30 AF XY: 0.00000209 AC XY: 1 AN XY: 478432

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: 0.00000142

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;T;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.69	.;N;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.58	N;N;N;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.98, 0.99	.;D;.;D;D
Vest4		0.54
MutPred		0.15		.;Gain of glycosylation at S518 (P = 0.1049);.;.;.;
MVP		0.38
MPC		1.0
ClinPred		0.84	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-101947025;