7-94911215-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001166160.2(PPP1R9A):c.1102G>A(p.Asp368Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 1,614,166 control chromosomes in the GnomAD database, including 4,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (224 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3804 hom.)
• Consequence: PPP1R9A NM_001166160.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.23

Genes affected

PPP1R9A (HGNC:14946): (protein phosphatase 1 regulatory subunit 9A) This gene is imprinted, and located in a cluster of imprinted genes on chromosome 7q12. This gene is transcribed in both neuronal and multiple embryonic tissues, and it is maternally expressed mainly in embryonic skeletal muscle tissues and biallelically expressed in other embryonic tissues. The protein encoded by this gene includes a PDZ domain and a sterile alpha motif (SAM). It is a regulatory subunit of protein phosphatase I, and controls actin cytoskeleton reorganization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021518767).
• BP6: Variant 7-94911215-G-A is Benign according to our data. Variant chr7-94911215-G-A is described in ClinVar as [Benign]. Clinvar id is 3059917.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R9A	NM_001166160.2	c.1102G>A	p.Asp368Asn	missense_variant	2/20	ENST00000433360.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R9A	ENST00000433360.6	c.1102G>A	p.Asp368Asn	missense_variant	2/20	1	NM_001166160.2

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7215 AN: 152200 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0359

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0489 AC: 12284 AN: 251312 Hom.: 387 AF XY: 0.0492 AC XY: 6684 AN XY: 135814

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0400

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0627

Gnomad NFE exome AF: 0.0763

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0678 AC: 99086 AN: 1461848 Hom.: 3804 Cov.: 33 AF XY: 0.0664 AC XY: 48317 AN XY: 727228

Gnomad4 AFR exome AF: 0.00974

Gnomad4 AMR exome AF: 0.0260

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0169

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.0796

Gnomad4 OTH exome AF: 0.0517

GnomAD4 genome AF: 0.0474 AC: 7215 AN: 152318 Hom.: 224 Cov.: 32 AF XY: 0.0453 AC XY: 3376 AN XY: 74488

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0359

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0650

Gnomad4 NFE AF: 0.0751

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0666 Hom.: 626

Bravo AF: 0.0439

TwinsUK AF: 0.0858 AC: 318

ALSPAC AF: 0.0906 AC: 349

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.0677 AC: 582

ExAC AF: 0.0492 AC: 5978

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP1R9A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D;D;.;.;D;D
MetaRNN	Benign	0.0022	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L
MutationTaster	Benign	0.62	D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.18	T;T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T
Polyphen		0.0010	.;B;.;B;.;.
Vest4		0.093
MPC		0.16
ClinPred		0.016	T
GERP RS		4.5
Varity_R		0.042
gMVP		0.15

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: rs61737465; hg19: chr7-94540527;