10-73495883-C-A

Variant names:

• chr10-73495883-C-A
• rs2057216990
• NM_021132.4:c.7G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_021132.4(PPP3CB):​c.7G>T​(p.Ala3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000534 in 935,706 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: 30)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: PPP3CB NM_021132.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

Genes affected

PPP3CB (HGNC:9315): (protein phosphatase 3 catalytic subunit beta) Enables several functions, including calmodulin binding activity; calmodulin-dependent protein phosphatase activity; and protein phosphatase 2B binding activity. Involved in calcineurin-NFAT signaling cascade; positive regulation of transcription by RNA polymerase II; and protein dephosphorylation. Located in cytoplasm. Part of calcineurin complex. Implicated in aortic valve stenosis. Biomarker of focal segmental glomerulosclerosis and schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

PPP3CB-AS1 (HGNC:50750): (PPP3CB antisense RNA 1 (head to head))

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12360287).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CB	NM_021132.4	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 14	ENST00000360663.10	NP_066955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CB	ENST00000360663.10	c.7G>T	p.Ala3Ser	missense_variant	Exon 1 of 14	1	NM_021132.4	ENSP00000353881.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000534 AC: 5 AN: 935706 Hom.: 0 Cov.: 25 AF XY: 0.00000654 AC XY: 3 AN XY: 458658

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: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>T (p.A3S) alteration is located in exon 1 (coding exon 1) of the PPP3CB gene. This alteration results from a G to T substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T;.;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.76	N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.95	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.12	B;B;.;.
Vest4		0.20
MutPred		0.25		Gain of phosphorylation at A3 (P = 9e-04);Gain of phosphorylation at A3 (P = 9e-04);Gain of phosphorylation at A3 (P = 9e-04);Gain of phosphorylation at A3 (P = 9e-04);
MVP		0.33
MPC		0.55
ClinPred		0.30	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.39

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: rs2057216990; hg19: chr10-75255641;