3-136001821-A-G

Position:

• chr3-136001821-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002718.5(PPP2R3A):​c.323A>G​(p.Asn108Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00392 in 1,614,154 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.11

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041802824).
• BP6: Variant 3-136001821-A-G is Benign according to our data. Variant chr3-136001821-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3038993.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00393 (5740/1461822) while in subpopulation MID AF= 0.0215 (124/5768). AF 95% confidence interval is 0.0184. There are 19 homozygotes in gnomad4_exome. There are 2865 alleles in male gnomad4_exome subpopulation. Median coverage is 42. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R3A	NM_002718.5	c.323A>G	p.Asn108Ser	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.323A>G	p.Asn108Ser	missense_variant	2/14	1	NM_002718.5	ENSP00000264977	P3
PPP2R3A	ENST00000490467.5	c.-213-25011A>G		intron_variant		2		ENSP00000419344

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00327 AC: 820 AN: 250578 Hom.: 3 AF XY: 0.00336 AC XY: 455 AN XY: 135436

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00483

Gnomad OTH exome AF: 0.00721

GnomAD4 exome AF: 0.00393 AC: 5740 AN: 1461822 Hom.: 19 Cov.: 42 AF XY: 0.00394 AC XY: 2865 AN XY: 727198

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74488

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00493 Hom.: 5

Bravo AF: 0.00431

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00688

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

Apr 25, 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	0.074
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.69
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.076
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.058	B
Vest4		0.32
MVP		0.043
MPC		0.34
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.071
gMVP		0.092

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: rs36020282; hg19: chr3-135720663;