rs8192687

chr7-113918864-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002711.4(PPP1R3A):c.133G>A(p.Gly45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 1,613,728 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (66 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.94

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061822236).
• BP6: Variant 7-113918864-C-T is Benign according to our data. Variant chr7-113918864-C-T is described in ClinVar as [Benign]. Clinvar id is 549524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-113918864-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 7 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R3A	NM_002711.4	c.133G>A	p.Gly45Ser	missense_variant	1/4	ENST00000284601.4
PPP1R3A	XM_005250473.4	c.51G>A	p.Glu17=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.133G>A	p.Gly45Ser	missense_variant	1/4	1	NM_002711.4	P1
PPP1R3A	ENST00000284602.1	c.133G>A	p.Gly45Ser	missense_variant, NMD_transcript_variant	1/5	1
PPP1R3A	ENST00000449795.5	c.-181-36544G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 900 AN: 152016 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00688

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00716 AC: 1796 AN: 250724 Hom.: 16 AF XY: 0.00750 AC XY: 1016 AN XY: 135488

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.00754

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00629 AC: 9188 AN: 1461594 Hom.: 66 Cov.: 31 AF XY: 0.00641 AC XY: 4659 AN XY: 727108

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00886

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00592 AC: 900 AN: 152134 Hom.: 7 Cov.: 32 AF XY: 0.00682 AC XY: 507 AN XY: 74380

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.00688

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00588 Hom.: 4

Bravo AF: 0.00341

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00703 AC: 854

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00524

EpiControl AF: 0.00640

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: BP4 (6 predictors for BP4, 4 predictors for PP3=not using, REVEL=0.061), BS1 (1.23% in 1000G-SAS, 2.56% in ExAC-Fin), BS2 (112 cases and 105 controls in type2diabetesgenetics.org)=benign -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.92	D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.061
Sift	Benign	0.15	T
Sift4G	Benign	0.082	T
Polyphen		0.11	B
Vest4		0.11
MVP		0.46
MPC		0.049
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.057
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs8192687; hg19: chr7-113558919; COSMIC: COSV52892253;