chr10-73479463-T-A

Position:

• chr10-73479463-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001289969.2(PPP3CB):​c.-119A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000752 in 1,461,812 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: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PPP3CB NM_001289969.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CB	NM_021132.4	c.140A>T	p.Asp47Val	missense_variant	2/14	ENST00000360663.10	NP_066955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CB	ENST00000360663.10	c.140A>T	p.Asp47Val	missense_variant	2/14	1	NM_021132.4	ENSP00000353881.5
PPP3CB	ENST00000394829.6	c.140A>T	p.Asp47Val	missense_variant	2/14	1		ENSP00000378306.2
PPP3CB	ENST00000394828.6	c.140A>T	p.Asp47Val	missense_variant	2/13	1		ENSP00000378305.2
PPP3CB	ENST00000342558.3	c.140A>T	p.Asp47Val	missense_variant	2/12	5		ENSP00000343147.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727210

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2023

The c.140A>T (p.D47V) alteration is located in exon 2 (coding exon 2) of the PPP3CB gene. This alteration results from a A to T substitution at nucleotide position 140, causing the aspartic acid (D) at amino acid position 47 to be replaced by a valine (V). 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	0.26
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.013	B;B;.;.
Vest4		0.47
MutPred		0.53		Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);
MVP		0.24
MPC		0.89
ClinPred		0.76	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762418445; hg19: chr10-75239221;