rs527638422

Variant names:

• chr7-113879105-CCT-C
• rs527638422
• NM_002711.4:c.1985_1986delAG

Variant summary

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

The NM_002711.4(PPP1R3A):​c.1985_1986delAG​(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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:4
• Conservation: PhyloP100: 1.90

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 19 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R3A	NM_002711.4	c.1985_1986delAG	p.Gln662ArgfsTer7	frameshift_variant	Exon 4 of 4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4	c.1382_1383delAG	p.Gln461ArgfsTer7	frameshift_variant	Exon 5 of 5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.1985_1986delAG	p.Gln662ArgfsTer7	frameshift_variant	Exon 4 of 4	1	NM_002711.4	ENSP00000284601.3

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 151940 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00227 AC XY: 307 AN XY: 135458

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.: 19 AF XY: 0.00380 AC XY: 2761 AN XY: 727110

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.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74328

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.: 1

Bravo AF: 0.00246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00415

EpiControl AF: 0.00409

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

INSULIN RESISTANCE, SEVERE, DIGENIC Pathogenic:1

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

DIABETES MELLITUS, TYPE II, DIGENIC Pathogenic:1

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

May 11, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Monogenic diabetes Uncertain:1

Nov 21, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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 -

Computational scores

Source: dbNSFP v4.3

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: rs527638422; hg19: chr7-113519160; COSMIC: COSV52890887; COSMIC: COSV52890887;