3-136001697-G-A

Position:

• chr3-136001697-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002718.5(PPP2R3A):​c.199G>A​(p.Asp67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,080 control chromosomes in the GnomAD database, including 46 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 (★). 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. D67G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (21 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03

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=0.0027314126).
• BP6: Variant 3-136001697-G-A is Benign according to our data. Variant chr3-136001697-G-A is described in ClinVar as [Benign]. Clinvar id is 3038062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1647/152282) while in subpopulation AFR AF= 0.0366 (1522/41546). AF 95% confidence interval is 0.0351. There are 25 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP2R3A	NM_002718.5	c.199G>A	p.Asp67Asn	missense_variant	2/14	ENST00000264977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.199G>A	p.Asp67Asn	missense_variant	2/14	1	NM_002718.5	P3
PPP2R3A	ENST00000490467.5	c.-213-25135G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1644 AN: 152164 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00318 AC: 798 AN: 251090 Hom.: 11 AF XY: 0.00242 AC XY: 329 AN XY: 135686

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00142 AC: 2083 AN: 1461798 Hom.: 21 Cov.: 31 AF XY: 0.00132 AC XY: 958 AN XY: 727192

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00363

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.0108 AC: 1647 AN: 152282 Hom.: 25 Cov.: 33 AF XY: 0.0107 AC XY: 796 AN XY: 74450

Gnomad4 AFR AF: 0.0366

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00236 Hom.: 8

Bravo AF: 0.0118

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0343 AC: 151

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00388 AC: 471

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000652

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

Sep 25, 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	0.081
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.060
Sift	Benign	0.55	T
Sift4G	Benign	0.60	T
Polyphen		0.0030	B
Vest4		0.19
MVP		0.068
MPC		0.38
ClinPred		0.0081	T
GERP RS		4.9
Varity_R		0.034
gMVP		0.14

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: rs57374999; hg19: chr3-135720539;