rs9814557

Positions:

• chr3-136001698-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002718.5(PPP2R3A):​c.200A>G​(p.Asp67Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 1,613,762 control chromosomes in the GnomAD database, including 73,912 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D67N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4882 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69030 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.33

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]

PPP2R3A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041641295).
• BP6: Variant 3-136001698-A-G is Benign according to our data. Variant chr3-136001698-A-G is described in ClinVar as [Benign]. Clinvar id is 3055861.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R3A	NM_002718.5	c.200A>G	p.Asp67Gly	missense_variant	2/14	ENST00000264977.8	NP_002709.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.200A>G	p.Asp67Gly	missense_variant	2/14	1	NM_002718.5	ENSP00000264977.3
PPP2R3A	ENST00000490467.5	c.-213-25134A>G		intron_variant		2		ENSP00000419344.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35137 AN: 152010 Hom.: 4885 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.229

GnomAD3 exomes AF: 0.252 AC: 63197 AN: 250856 Hom.: 9460 AF XY: 0.264 AC XY: 35814 AN XY: 135546

Gnomad AFR exome AF: 0.0966

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.299 AC: 436365 AN: 1461634 Hom.: 69030 Cov.: 45 AF XY: 0.300 AC XY: 218463 AN XY: 727116

Gnomad4 AFR exome AF: 0.0924

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.0194

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.231 AC: 35131 AN: 152128 Hom.: 4882 Cov.: 32 AF XY: 0.229 AC XY: 17047 AN XY: 74350

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.346

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.229

Alfa AF: 0.295 Hom.: 13353

Bravo AF: 0.217

TwinsUK AF: 0.320 AC: 1186

ALSPAC AF: 0.338 AC: 1301

ESP6500AA AF: 0.102 AC: 448

ESP6500EA AF: 0.313 AC: 2694

ExAC AF: 0.254 AC: 30793

Asia WGS AF: 0.140 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as 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	0.10
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.042
Sift	Uncertain	0.013	D
Sift4G	Benign	0.12	T
Polyphen		0.085	B
Vest4		0.11
MPC		0.43
ClinPred		0.023	T
GERP RS		3.3
Varity_R		0.12
gMVP		0.22

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: rs9814557; hg19: chr3-135720540; COSMIC: COSV53861573;