Variant rs527638422 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002711.4(PPP1R3A):c.1985_1986del(p.Gln662ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,613,644 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 19 hom. )

Consequence

PPP1R3A
NM_002711.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:3

Conservation

PhyloP100: 1.90

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome at 3 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R3A	NM_002711.4 linkuse as main transcript	c.1985_1986del	p.Gln662ArgfsTer7	frameshift_variant	4/4	ENST00000284601.4
PPP1R3A	XM_005250473.4 linkuse as main transcript	c.1382_1383del	p.Gln461ArgfsTer7	frameshift_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R3A	ENST00000284601.4 linkuse as main transcript	c.1985_1986del	p.Gln662ArgfsTer7	frameshift_variant	4/4	1	NM_002711.4	P1	Q16821-1

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00229

AC:

574

AN:

250724

Hom.:

AF XY:

0.00227

AC XY:

307

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00448

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00393

AC:

5749

AN:

1461586

Hom.:

AF XY:

0.00380

AC XY:

2761

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00496

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00264

AC:

402

AN:

152058

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00481

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000775

Hom.:

Bravo

AF:

0.00246

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00415

EpiControl

AF:

0.00409

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diabetes mellitus, type II, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Insulin resistance, severe, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 11, 2016

- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Nov 21, 2018

ACMG criteria: PVS1 (not sure whether frameshift, not sure whether LOF of PPP1R3A is a known mechanism for disease since there is only one report and in this report the deletion could be a modifier ) Variant reported in PMID 12118251: PPARG/PPP1R3A digenic inheritance; BS2 (3 homozygotes in gnomAD NFE)=VUS -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PPP1R3A p.Gln662Argfs*7 variant was not identified in the literature but was identified in dbSNP (ID: rs527638422), ClinVar (classified as a VUS by Genetic Services Laboratory, University of Chicago), Cosmic and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 647 of 282108 chromosomes (3 homozygous) at a frequency of 0.002293 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 563 of 128528 chromosomes (freq: 0.00438), Other in 12 of 7206 chromosomes (freq: 0.001665), European (Finnish) in 34 of 25120 chromosomes (freq: 0.001354), African in 24 of 24962 chromosomes (freq: 0.000962) and Latino in 14 of 35390 chromosomes (freq: 0.000396), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The c.1985_1986del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 662 and leads to a premature stop codon 7 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the PPP1R3A gene are not a known mechanism of disease. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over