3-136002243-A-G

Position:

• chr3-136002243-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000264977.8(PPP2R3A):​c.745A>G​(p.Ile249Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,613,918 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (61 hom.)
• Consequence: PPP2R3A ENST00000264977.8 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 8.94

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008845568).
• BP6: Variant 3-136002243-A-G is Benign according to our data. Variant chr3-136002243-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3044322.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R3A	NM_002718.5	c.745A>G	p.Ile249Val	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.745A>G	p.Ile249Val	missense_variant	2/14	1	NM_002718.5	ENSP00000264977	P3
PPP2R3A	ENST00000490467.5	c.-213-24589A>G		intron_variant		2		ENSP00000419344

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152236 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00951

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00495 AC: 1229 AN: 248292 Hom.: 9 AF XY: 0.00490 AC XY: 659 AN XY: 134548

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00853

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00824 AC: 12049 AN: 1461564 Hom.: 61 Cov.: 37 AF XY: 0.00791 AC XY: 5754 AN XY: 727060

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00646

Gnomad4 NFE exome AF: 0.00998

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152354 Hom.: 3 Cov.: 32 AF XY: 0.00482 AC XY: 359 AN XY: 74492

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00951

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00793 Hom.: 6

Bravo AF: 0.00493

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.00511 AC: 621

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00747

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

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	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.069	T
Polyphen		0.99	D
Vest4		0.45
MVP		0.32
MPC		0.31
ClinPred		0.043	T
GERP RS		5.2
Varity_R		0.31
gMVP		0.30

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: rs115951794; hg19: chr3-135721085;