7-94911104-A-G

Position:

• chr7-94911104-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166160.2(PPP1R9A):​c.991A>G​(p.Met331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,614,054 control chromosomes in the GnomAD database, including 8,078 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2694 hom., cov: 32)
  • Exomes 𝑓: 0.061 (5384 hom.)
• Consequence: PPP1R9A NM_001166160.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.625

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036401749).
• BP6: Variant 7-94911104-A-G is Benign according to our data. Variant chr7-94911104-A-G is described in ClinVar as [Benign]. Clinvar id is 1282072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R9A	NM_001166160.2	c.991A>G	p.Met331Val	missense_variant	2/20	ENST00000433360.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R9A	ENST00000433360.6	c.991A>G	p.Met331Val	missense_variant	2/20	1	NM_001166160.2

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21207 AN: 152072 Hom.: 2678 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.0979 AC: 24610 AN: 251440 Hom.: 2122 AF XY: 0.0909 AC XY: 12359 AN XY: 135898

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0402

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0612 AC: 89487 AN: 1461864 Hom.: 5384 Cov.: 32 AF XY: 0.0615 AC XY: 44728 AN XY: 727232

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.0375

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0408

Gnomad4 NFE exome AF: 0.0396

Gnomad4 OTH exome AF: 0.0803

GnomAD4 genome AF: 0.140 AC: 21269 AN: 152190 Hom.: 2694 Cov.: 32 AF XY: 0.141 AC XY: 10464 AN XY: 74412

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0404

Gnomad4 OTH AF: 0.128

Alfa AF: 0.0621 Hom.: 1626

Bravo AF: 0.155

TwinsUK AF: 0.0380 AC: 141

ALSPAC AF: 0.0441 AC: 170

ESP6500AA AF: 0.321 AC: 1416

ESP6500EA AF: 0.0419 AC: 360

ExAC AF: 0.0980 AC: 11904

Asia WGS AF: 0.219 AC: 763 AN: 3478

EpiCase AF: 0.0394

EpiControl AF: 0.0454

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2021	This variant is associated with the following publications: (PMID: 25889363) -

PPP1R9A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 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	0.060
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.9
DANN	Benign	0.37
DEOGEN2	Benign	0.029	.;T;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.68	T;T;.;.;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N;N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.12	N;N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.25	T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T
Polyphen		0.0	.;B;.;B;.;.
Vest4		0.045
MPC		0.17
ClinPred		0.0022	T
GERP RS		0.33
Varity_R		0.042
gMVP		0.13

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: rs10230714; hg19: chr7-94540416; COSMIC: COSV56912555; COSMIC: COSV56912555;