Genetic Variant NM_001164161.2:c.854G>A (chr11-68564311-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001164161.2(PPP6R3):c.854G>A(p.Gly285Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G285C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPP6R3
NM_001164161.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

Genes affected

PPP6R3 (HGNC:1173): (protein phosphatase 6 regulatory subunit 3) Protein phosphatase regulatory subunits, such as SAPS3, modulate the activity of protein phosphatase catalytic subunits by restricting substrate specificity, recruiting substrates, and determining the intracellular localization of the holoenzyme. SAPS3 is a regulatory subunit for the protein phosphatase-6 catalytic subunit (PPP6C; MIM 612725) (Stefansson and Brautigan, 2006 [PubMed 16769727]).[supplied by OMIM, Nov 2010]

PPP6R3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164161.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP6R3	NM_001164161.2	MANE Select	c.854G>A	p.Gly285Asp	missense	Exon 9 of 24	NP_001157633.1	Q5H9R7-1
PPP6R3	NM_001352354.2		c.854G>A	p.Gly285Asp	missense	Exon 10 of 26	NP_001339283.1
PPP6R3	NM_001352356.2		c.854G>A	p.Gly285Asp	missense	Exon 9 of 25	NP_001339285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP6R3	ENST00000393800.7	TSL:1 MANE Select	c.854G>A	p.Gly285Asp	missense	Exon 9 of 24	ENSP00000377389.2	Q5H9R7-1
PPP6R3	ENST00000393801.7	TSL:1	c.854G>A	p.Gly285Asp	missense	Exon 9 of 25	ENSP00000377390.3	Q5H9R7-5
PPP6R3	ENST00000524904.5	TSL:1	c.854G>A	p.Gly285Asp	missense	Exon 9 of 24	ENSP00000433058.1	Q5H9R7-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

250138

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725548

African (AFR)

AF:

0.00

AC:

AN:

33374

American (AMR)

AF:

0.00

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

85956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109278

Other (OTH)

AF:

0.00

AC:

AN:

60226

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.72

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.8

PhyloP100

8.0

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.63

Sift

Uncertain

0.0080

Sift4G

Benign

0.071

Polyphen

0.76

Vest4

0.69

MutPred

0.56

Loss of catalytic residue at E284 (P = 0.1059)

MVP

0.64

MPC

0.52

ClinPred

0.95

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.70

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over