rs1800000

Positions:

• chr7-113878443-C-A
• chr7-113878443-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.2649G>T​(p.Arg883Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,612,206 control chromosomes in the GnomAD database, including 825 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 0.017 (111 hom., cov: 32)
  • Exomes 𝑓: 0.012 (714 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.891

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=3.697574E-4).
• BP6: Variant 7-113878443-C-A is Benign according to our data. Variant chr7-113878443-C-A is described in ClinVar as [Benign]. Clinvar id is 549519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-113878443-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R3A	NM_002711.4	c.2649G>T	p.Arg883Ser	missense_variant	4/4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4	c.2046G>T	p.Arg682Ser	missense_variant	5/5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.2649G>T	p.Arg883Ser	missense_variant	4/4	1	NM_002711.4	ENSP00000284601	P1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2630 AN: 151958 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0824

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00421

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0319 AC: 7947 AN: 249312 Hom.: 423 AF XY: 0.0278 AC XY: 3747 AN XY: 134798

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.0727

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.0830

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0117 AC: 17126 AN: 1460130 Hom.: 714 Cov.: 33 AF XY: 0.0112 AC XY: 8120 AN XY: 726430

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0696

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.00481

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0173 AC: 2633 AN: 152076 Hom.: 111 Cov.: 32 AF XY: 0.0217 AC XY: 1610 AN XY: 74342

Gnomad4 AFR AF: 0.00251

Gnomad4 AMR AF: 0.0374

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0824

Gnomad4 NFE AF: 0.00421

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00886 Hom.: 101

Bravo AF: 0.0161

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.0283 AC: 3437

Asia WGS AF: 0.0520 AC: 180 AN: 3474

EpiCase AF: 0.00235

EpiControl AF: 0.00296

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

Feb 15, 2019

ACMG criteria: BP4 (REVEL 0.016 + 10 predictors), BA1 (14% in gnomAD EA, 3% overall MAF, 0.5% ENF, 8% EF), BS2 (1549 cases and 1668 controls in type2diabetesgenetics.org), BP5 (alternate cause identified): benign -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.034
DANN	Benign	0.38
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.00037	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.016
Sift	Benign	0.26	T
Sift4G	Benign	0.76	T
Polyphen		0.0050	B
Vest4		0.029
MutPred		0.17		Gain of phosphorylation at R883 (P = 0.0209);
MPC		0.048
ClinPred		0.0026	T
GERP RS		-3.9
Varity_R		0.071
gMVP		0.069

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: rs1800000; hg19: chr7-113518498; COSMIC: COSV52878887; COSMIC: COSV52878887;