chr7-113878102-A-C

Position:

• chr7-113878102-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002711.4(PPP1R3A):​c.2990T>G​(p.Phe997Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,613,378 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: PPP1R3A NM_002711.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011568487).
• BP6: Variant 7-113878102-A-C is Benign according to our data. Variant chr7-113878102-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 549557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-113878102-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R3A	NM_002711.4	c.2990T>G	p.Phe997Cys	missense_variant	4/4	ENST00000284601.4	NP_002702.2
PPP1R3A	XM_005250473.4	c.2387T>G	p.Phe796Cys	missense_variant	5/5		XP_005250530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R3A	ENST00000284601.4	c.2990T>G	p.Phe997Cys	missense_variant	4/4	1	NM_002711.4	ENSP00000284601	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 151956 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00136 AC: 339 AN: 250096 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 135304

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00192 AC: 2811 AN: 1461304 Hom.: 2 Cov.: 31 AF XY: 0.00188 AC XY: 1366 AN XY: 726970

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00155 AC: 235 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74338

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00155

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00119 AC: 145

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 10, 2017

ACMG Criteria:BP4 (7 predictors), BS2 (10 cases and 9 controls in T2DM) -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.064
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.32
MVP		0.56
MPC		0.29
ClinPred		0.025	T
GERP RS		1.4
Varity_R		0.16
gMVP		0.36

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: rs35572169; hg19: chr7-113518157; COSMIC: COSV105123217; COSMIC: COSV105123217;