7-113878048-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002711.4(PPP1R3A):c.3044A>G(p.Asn1015Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,348 control chromosomes in the GnomAD database, including 27 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 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.214

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026070774).
• BP6: Variant 7-113878048-T-C is Benign according to our data. Variant chr7-113878048-T-C is described in ClinVar as [Benign]. Clinvar id is 393400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00735 (1118/152046) while in subpopulation AFR AF= 0.0249 (1032/41504). AF 95% confidence interval is 0.0236. There are 13 homozygotes in gnomad4. There are 515 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R3A	NM_002711.4	c.3044A>G	p.Asn1015Ser	missense_variant	4/4	ENST00000284601.4
PPP1R3A	XM_005250473.4	c.2441A>G	p.Asn814Ser	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.3044A>G	p.Asn1015Ser	missense_variant	4/4	1	NM_002711.4	P1

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1109 AN: 151928 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0247

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: 0.00478

GnomAD3 exomes AF: 0.00194 AC: 486 AN: 250532 Hom.: 4 AF XY: 0.00141 AC XY: 191 AN XY: 135408

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000728 AC: 1064 AN: 1461302 Hom.: 14 Cov.: 31 AF XY: 0.000615 AC XY: 447 AN XY: 726966

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00735 AC: 1118 AN: 152046 Hom.: 13 Cov.: 32 AF XY: 0.00693 AC XY: 515 AN XY: 74312

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: 0.00473

Alfa AF: 0.000915 Hom.: 2

Bravo AF: 0.00801

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00242 AC: 294

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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: BS2 (74 cases and 66 controls in T2DM), BA1 (2.6% MAF in gnomAD African)= benign; 4 homozygous in ExAC (REVEL 0.204 + 9 BP4 predictors: conflicting evidence, not using) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.87
Dann	Benign	0.099
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MVP		0.17
MPC		0.038
ClinPred		0.0038	T
GERP RS		3.5
Varity_R		0.030
gMVP		0.060

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: rs149701175; hg19: chr7-113518103;