rs35067467

chr7-113879212-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002711.4(PPP1R3A):c.1880G>A(p.Arg627Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,613,512 control chromosomes in the GnomAD database, including 449 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (241 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (208 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.484

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014230013).
• BP6: Variant 7-113879212-C-T is Benign according to our data. Variant chr7-113879212-C-T is described in ClinVar as [Benign]. Clinvar id is 393404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R3A	NM_002711.4	c.1880G>A	p.Arg627Lys	missense_variant	4/4	ENST00000284601.4
PPP1R3A	XM_005250473.4	c.1277G>A	p.Arg426Lys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.1880G>A	p.Arg627Lys	missense_variant	4/4	1	NM_002711.4	P1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4686 AN: 151958 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.00843 AC: 2114 AN: 250648 Hom.: 95 AF XY: 0.00614 AC XY: 831 AN XY: 135442

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00690

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00336 AC: 4904 AN: 1461436 Hom.: 208 Cov.: 71 AF XY: 0.00292 AC XY: 2122 AN XY: 727020

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00773

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000306

Gnomad4 OTH exome AF: 0.00734

GnomAD4 genome AF: 0.0309 AC: 4693 AN: 152076 Hom.: 241 Cov.: 32 AF XY: 0.0288 AC XY: 2138 AN XY: 74324

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.00689 Hom.: 68

Bravo AF: 0.0361

ESP6500AA AF: 0.103 AC: 455

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0101 AC: 1227

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 08, 2018

ACMG criteria: BA1 (10.7% in African), BS2 (142 homo in ExAC), BP4 (REVEL score 0.015 + 9 predictors)=benign -

PPP1R3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 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	0.087
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.15
Dann	Benign	0.54
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.74	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.015
Sift	Benign	0.32	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.044
ClinPred		0.0070	T
GERP RS		-3.9
Varity_R		0.043
gMVP		0.097

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: rs35067467; hg19: chr7-113519267;