3-136002009-G-T

Position:

• chr3-136002009-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002718.5(PPP2R3A):​c.511G>T​(p.Ala171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,636 control chromosomes in the GnomAD database, including 68,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (9982 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58870 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3720255E-5).
• BP6: Variant 3-136002009-G-T is Benign according to our data. Variant chr3-136002009-G-T is described in ClinVar as [Benign]. Clinvar id is 3059643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R3A	NM_002718.5	c.511G>T	p.Ala171Ser	missense_variant	2/14	ENST00000264977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.511G>T	p.Ala171Ser	missense_variant	2/14	1	NM_002718.5	P3
PPP2R3A	ENST00000490467.5	c.-213-24823G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52276 AN: 151878 Hom.: 9972 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.294 AC: 73668 AN: 250950 Hom.: 11499 AF XY: 0.289 AC XY: 39236 AN XY: 135616

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.307

Gnomad FIN exome AF: 0.316

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.280 AC: 408563 AN: 1461642 Hom.: 58870 Cov.: 67 AF XY: 0.280 AC XY: 203302 AN XY: 727116

Gnomad4 AFR exome AF: 0.529

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.227

Gnomad4 SAS exome AF: 0.311

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.344 AC: 52321 AN: 151994 Hom.: 9982 Cov.: 32 AF XY: 0.344 AC XY: 25558 AN XY: 74308

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.343

Alfa AF: 0.271 Hom.: 9169

Bravo AF: 0.347

TwinsUK AF: 0.268 AC: 992

ALSPAC AF: 0.273 AC: 1052

ESP6500AA AF: 0.506 AC: 2231

ESP6500EA AF: 0.275 AC: 2364

ExAC AF: 0.298 AC: 36143

Asia WGS AF: 0.262 AC: 913 AN: 3478

EpiCase AF: 0.260

EpiControl AF: 0.258

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.73
DANN	Benign	0.28
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.000034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.021
Sift	Benign	0.80	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.057
ClinPred		0.00013	T
GERP RS		0.066
Varity_R		0.041
gMVP		0.077

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: rs6779903; hg19: chr3-135720851; COSMIC: COSV53860999;