Genetic Variant PPP1R3A:p.Ala931Glu (chr7-113878300-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002711.4(PPP1R3A):c.2792C>A(p.Ala931Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,136 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

PPP1R3A
NM_002711.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.454

Publications

16 publications found

Variant links:

Genes affected

PPP1R3A (HGNC:9291): (protein phosphatase 1 regulatory subunit 3A) The glycogen-associated form of protein phosphatase-1 (PP1) derived from skeletal muscle is a heterodimer composed of a 37-kD catalytic subunit and a 124-kD targeting and regulatory subunit. This gene encodes the regulatory subunit which binds to muscle glycogen with high affinity, thereby enhancing dephosphorylation of glycogen-bound substrates for PP1 such as glycogen synthase and glycogen phosphorylase kinase. [provided by RefSeq, Jul 2008]

PPP1R3A Gene-Disease associations (from GenCC):

diabetes mellitus, noninsulin-dependent
Inheritance: Unknown Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PPP1R3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057417452).

BS2

High Homozygotes in GnomAdExome4 at 2 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R3A	NM_002711.4 link	c.2792C>A	p.Ala931Glu	missense_variant	Exon 4 of 4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4 link	c.2189C>A	p.Ala730Glu	missense_variant	Exon 5 of 5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4 link	c.2792C>A	p.Ala931Glu	missense_variant	Exon 4 of 4	1	NM_002711.4	ENSP00000284601.3

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00136

AC:

339

AN:

249668

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00225

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00193

AC:

2816

AN:

1461048

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1367

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33444

American (AMR)

AF:

0.00152

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.000958

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000940

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00230

AC:

2556

AN:

1111640

Other (OTH)

AF:

0.00176

AC:

106

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

163

327

490

654

817

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00155

AC:

235

AN:

152088

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

106

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41542

American (AMR)

AF:

0.00118

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

67944

Other (OTH)

AF:

0.00332

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00278

EpiControl

AF:

0.00296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.2

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.087

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.32

M_CAP

Benign

0.0023

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.76

PhyloP100

0.45

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.71

REVEL

Benign

0.017

Sift

Benign

0.33

Sift4G

Benign

0.96

Polyphen

0.0010

Vest4

0.063

MVP

0.18

MPC

0.049

ClinPred

0.0068

GERP RS

1.9

Varity_R

0.063

gMVP

0.19

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over