rs77456357

Positions:

• chr7-113877833-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002711.4(PPP1R3A):​c.3259A>G​(p.Ile1087Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,609,466 control chromosomes in the GnomAD database, including 28 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 0.0074 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.122

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=0.0032697022).
• BP6: Variant 7-113877833-T-C is Benign according to our data. Variant chr7-113877833-T-C is described in ClinVar as [Benign]. Clinvar id is 393399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00736 (1120/152104) while in subpopulation AFR AF= 0.0249 (1034/41536). AF 95% confidence interval is 0.0236. There are 14 homozygotes in gnomad4. There are 514 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R3A	NM_002711.4	c.3259A>G	p.Ile1087Val	missense_variant	4/4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4	c.2656A>G	p.Ile886Val	missense_variant	5/5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.3259A>G	p.Ile1087Val	missense_variant	4/4	1	NM_002711.4	ENSP00000284601	P1

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 1111 AN: 151986 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00467

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00194 AC: 485 AN: 249786 Hom.: 4 AF XY: 0.00141 AC XY: 190 AN XY: 135010

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000728 AC: 1061 AN: 1457362 Hom.: 14 Cov.: 30 AF XY: 0.000619 AC XY: 449 AN XY: 725310

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00736 AC: 1120 AN: 152104 Hom.: 14 Cov.: 32 AF XY: 0.00691 AC XY: 514 AN XY: 74362

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.00467

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00128 Hom.: 4

Bravo AF: 0.00800

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00241 AC: 293

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

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 21, 2018

ACMG criteria: BP4 (REVEL 0.027 + 10 predictors), BS2 (75 cases and 66 controls in T2DM), BA1 (2.6% MAF in gnomAD African)= 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	0.068
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.88
DANN	Benign	0.32
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MVP		0.31
MPC		0.039
ClinPred		0.0024	T
GERP RS		1.7
Varity_R		0.025
gMVP		0.15

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: rs77456357; hg19: chr7-113517888;