chr7-113878447-A-T

Variant names:

• chr7-113878447-A-T
• rs2974938
• NM_002711.4:c.2645T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002711.4(PPP1R3A):​c.2645T>A​(p.Leu882His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,612,496 control chromosomes in the GnomAD database, including 796,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72160 hom., cov: 32)
  • Exomes 𝑓: 1.0 (724152 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.15
• Publications: 30 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8340702E-6).
• BP6: Variant 7-113878447-A-T is Benign according to our data. Variant chr7-113878447-A-T is described in ClinVar as Benign. ClinVar VariationId is 1231102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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.2645T>A	p.Leu882His	missense	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.2645T>A	p.Leu882His	missense	Exon 4 of 4	ENSP00000284601.3

Frequencies

GnomAD3 genomes AF: 0.973 AC: 147975 AN: 152006 Hom.: 72121 Cov.: 32

Gnomad AFR AF: 0.914

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.972

GnomAD2 exomes AF: 0.991 AC: 247592 AN: 249766 AF XY: 0.993

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.986

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.990

GnomAD4 exome AF: 0.996 AC: 1454155 AN: 1460372 Hom.: 724152 Cov.: 73 AF XY: 0.996 AC XY: 723663 AN XY: 726546

African (AFR) AF: 0.912 AC: 30491 AN: 33442

American (AMR) AF: 0.990 AC: 44140 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 25722 AN: 26112

East Asian (EAS) AF: 1.00 AC: 39672 AN: 39672

South Asian (SAS) AF: 0.999 AC: 86162 AN: 86248

European-Finnish (FIN) AF: 1.00 AC: 52440 AN: 52446

Middle Eastern (MID) AF: 0.980 AC: 5644 AN: 5762

European-Non Finnish (NFE) AF: 0.999 AC: 1110238 AN: 1111738

Other (OTH) AF: 0.988 AC: 59646 AN: 60354

GnomAD4 genome AF: 0.973 AC: 148068 AN: 152124 Hom.: 72160 Cov.: 32 AF XY: 0.974 AC XY: 72414 AN XY: 74372

African (AFR) AF: 0.914 AC: 37942 AN: 41512

American (AMR) AF: 0.985 AC: 15009 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3418 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5149 AN: 5150

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10632 AN: 10632

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67843 AN: 67974

Other (OTH) AF: 0.972 AC: 2053 AN: 2112

Alfa AF: 0.993 Hom.: 46000

Bravo AF: 0.970

TwinsUK AF: 0.999 AC: 3704

ALSPAC AF: 0.998 AC: 3848

ESP6500AA AF: 0.912 AC: 4018

ESP6500EA AF: 0.998 AC: 8578

ExAC AF: 0.990 AC: 120164

EpiCase AF: 0.997

EpiControl AF: 0.996

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Type 2 diabetes mellitus Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PPP1R3A-related disorder Benign:1

Oct 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.010
DANN	Benign	0.27
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00084	N
LIST_S2	Benign	0.091	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.22	N
PhyloP100		-2.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.0070
Sift	Benign	0.29	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.032
MPC		0.052
ClinPred		0.016	T
GERP RS		-4.0
Varity_R		0.047
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs2974938; hg19: chr7-113518502; COSMIC: COSV99495035; COSMIC: COSV99495035;