rs1799999

Variant names:

• chr7-113878379-C-A
• rs1799999
• NM_002711.4:c.2713G>T

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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
• Publications: 62 publications found

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]

PPP1R3A Gene-Disease associations (from GenCC):

• diabetes mellitus, noninsulin-dependent

  Inheritance: Unknown Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 8706.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002711.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3A	NM_002711.4	MANE Select	c.2713G>T	p.Asp905Tyr	missense	Exon 4 of 4	NP_002702.2	Q16821-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3A	ENST00000284601.4	TSL:1 MANE Select	c.2713G>T	p.Asp905Tyr	missense	Exon 4 of 4	ENSP00000284601.3	Q16821-1

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

GnomAD2 exomes AF: 0.221 AC: 55132 AN: 249384 AF XY: 0.223

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 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

African (AFR) AF: 0.197 AC: 6583 AN: 33442

American (AMR) AF: 0.257 AC: 11460 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5630 AN: 26108

East Asian (EAS) AF: 0.688 AC: 27295 AN: 39676

South Asian (SAS) AF: 0.389 AC: 33521 AN: 86242

European-Finnish (FIN) AF: 0.194 AC: 10089 AN: 52076

Middle Eastern (MID) AF: 0.165 AC: 952 AN: 5762

European-Non Finnish (NFE) AF: 0.0908 AC: 100924 AN: 1111622

Other (OTH) AF: 0.170 AC: 10242 AN: 60356

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

African (AFR) AF: 0.193 AC: 8020 AN: 41472

American (AMR) AF: 0.214 AC: 3266 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 716 AN: 3466

East Asian (EAS) AF: 0.671 AC: 3435 AN: 5122

South Asian (SAS) AF: 0.398 AC: 1917 AN: 4812

European-Finnish (FIN) AF: 0.204 AC: 2153 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0950 AC: 6456 AN: 67928

Other (OTH) AF: 0.180 AC: 377 AN: 2100

Alfa AF: 0.136 Hom.: 8522

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	PPP1R3A-related disorder (1)
-	1	-	Type 2 diabetes mellitus (1)
-	-	-	Insulin resistance, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.2
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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