chr3-136001730-G-A

Position:

• chr3-136001730-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002718.5(PPP2R3A):​c.232G>A​(p.Gly78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,614,088 control chromosomes in the GnomAD database, including 22 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (21 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.16

Genes affected

PPP2R3A (HGNC:9307): (protein phosphatase 2 regulatory subunit B''alpha) This gene encodes one of the regulatory subunits of the protein phosphatase 2. Protein phosphatase 2 (formerly named type 2A) is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2 holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B. The regulatory subunit is encoded by a diverse set of genes that have been grouped into the B/PR55, B'/PR61, and B''/PR72 families. These different regulatory subunits confer distinct enzymatic specificities and intracellular localizations to the holozenzyme. The product of this gene belongs to the B'' family. The B'' family has been further divided into subfamilies. The product of this gene belongs to the alpha subfamily of regulatory subunit B''. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047598183).
• BP6: Variant 3-136001730-G-A is Benign according to our data. Variant chr3-136001730-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3034364.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-136001730-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R3A	NM_002718.5	c.232G>A	p.Gly78Arg	missense_variant	2/14	ENST00000264977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.232G>A	p.Gly78Arg	missense_variant	2/14	1	NM_002718.5	P3
PPP2R3A	ENST00000490467.5	c.-213-25102G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00484

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00277 AC: 696 AN: 250952 Hom.: 1 AF XY: 0.00303 AC XY: 411 AN XY: 135620

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00500

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00452 AC: 6604 AN: 1461794 Hom.: 21 Cov.: 45 AF XY: 0.00443 AC XY: 3225 AN XY: 727188

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74472

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00484

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00500 Hom.: 7

Bravo AF: 0.00273

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00260 AC: 315

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.27
MutPred		0.42		Gain of phosphorylation at S81 (P = 0.0817);
MVP		0.13
MPC		0.41
ClinPred		0.026	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs145130777; hg19: chr3-135720572; COSMIC: COSV53862494;