rs61756423

Positions:

• chr7-113879177-C-A

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.1915G>T​(p.Gly639Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,613,586 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (53 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.29

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=0.0049847662).
• BP6: Variant 7-113879177-C-A is Benign according to our data. Variant chr7-113879177-C-A is described in ClinVar as [Benign]. Clinvar id is 393403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-113879177-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R3A	NM_002711.4	c.1915G>T	p.Gly639Cys	missense_variant	4/4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4	c.1312G>T	p.Gly438Cys	missense_variant	5/5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.1915G>T	p.Gly639Cys	missense_variant	4/4	1	NM_002711.4	ENSP00000284601	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 151994 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00733

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00484 AC: 1214 AN: 250568 Hom.: 3 AF XY: 0.00473 AC XY: 640 AN XY: 135418

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00557

GnomAD4 exome AF: 0.00627 AC: 9157 AN: 1461474 Hom.: 53 Cov.: 71 AF XY: 0.00601 AC XY: 4373 AN XY: 727050

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00632

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00715

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00465 AC: 707 AN: 152112 Hom.: 6 Cov.: 32 AF XY: 0.00468 AC XY: 348 AN XY: 74356

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00733

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00646 Hom.: 8

Bravo AF: 0.00377

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00479 AC: 581

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00593

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

Dec 07, 2018

ACMG criteria: BP4 (REVEL 0.122 + BP4/6 predictors, not using PP3/2 predictors), BS2 (65 cases and 59 controls in T2DM), BS1 (overall MAF in gnomAD is 0.5%): benign -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.074	T
Polyphen		0.98	D
Vest4		0.15
MVP		0.53
MPC		0.14
ClinPred		0.026	T
GERP RS		5.1
Varity_R		0.14
gMVP		0.16

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: rs61756423; hg19: chr7-113519232;