rs527638422

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 8 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 19 Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3A	NM_002711.4	MANE Select	c.1985_1986delAG	p.Gln662ArgfsTer7	frameshift	Exon 4 of 4	NP_002702.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3A	ENST00000284601.4	TSL:1 MANE Select	c.1985_1986delAG	p.Gln662ArgfsTer7	frameshift	Exon 4 of 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

GnomAD2 exomes AF: 0.00229 AC: 574 AN: 250724 AF XY: 0.00227

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 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

African (AFR) AF: 0.000687 AC: 23 AN: 33460

American (AMR) AF: 0.000358 AC: 16 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00496 AC: 5513 AN: 1111812

Other (OTH) AF: 0.00197 AC: 119 AN: 60384

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74328

African (AFR) AF: 0.00120 AC: 50 AN: 41508

American (AMR) AF: 0.000394 AC: 6 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 67962

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	DIABETES MELLITUS, TYPE II, DIGENIC (1)
1	-	-	INSULIN RESISTANCE, SEVERE, DIGENIC (1)
-	1	-	Monogenic diabetes (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=34/166	disease causing (ClinVar)

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