rs1799999

chr7-113878379-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002711.4(PPP1R3A):c.2713G>T(p.Asp905Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,611,778 control chromosomes in the GnomAD database, including 29,281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (3429 hom., cov: 32)
  • Exomes 𝑓: 0.14 (25852 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 3.23

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.817586E-6).
• BP6: Variant 7-113878379-C-A is Benign according to our data. Variant chr7-113878379-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8706.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr7-113878379-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R3A	NM_002711.4	c.2713G>T	p.Asp905Tyr	missense_variant	4/4	ENST00000284601.4
PPP1R3A	XM_005250473.4	c.2110G>T	p.Asp704Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.2713G>T	p.Asp905Tyr	missense_variant	4/4	1	NM_002711.4	P1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26465 AN: 151784 Hom.: 3426 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.221 AC: 55132 AN: 249384 Hom.: 9572 AF XY: 0.223 AC XY: 30090 AN XY: 134852

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.684

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.0985

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.142 AC: 206696 AN: 1459874 Hom.: 25852 Cov.: 33 AF XY: 0.149 AC XY: 107979 AN XY: 726318

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.688

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.0908

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.174 AC: 26493 AN: 151904 Hom.: 3429 Cov.: 32 AF XY: 0.188 AC XY: 13954 AN XY: 74244

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.0950

Gnomad4 OTH AF: 0.180

Alfa AF: 0.133 Hom.: 4276

Bravo AF: 0.178

TwinsUK AF: 0.0914 AC: 339

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.195 AC: 858

ESP6500EA AF: 0.105 AC: 902

ExAC AF: 0.219 AC: 26546

Asia WGS AF: 0.439 AC: 1524 AN: 3478

EpiCase AF: 0.0978

EpiControl AF: 0.0986

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: BP6,PP5. This variant was detected in homozygous state. -

PPP1R3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 7581368) -

Insulin resistance, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0000088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.84	P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		0.98	D
Vest4		0.15
MPC		0.31
ClinPred		0.044	T
GERP RS		5.6
Varity_R		0.20
gMVP		0.37

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: rs1799999; hg19: chr7-113518434; COSMIC: COSV52878180; COSMIC: COSV52878180;