Variant 11-68558570-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001164161.2(PPP6R3):c.736G>A(p.Glu246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

PPP6R3
NM_001164161.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56

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:

PPP6R3 (HGNC:):

PPP6R3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP6R3	NM_001164161.2 linkuse as main transcript	c.736G>A	p.Glu246Lys	missense_variant	8/24	ENST00000393800.7	NP_001157633.1	Q5H9R7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP6R3	ENST00000393800.7 linkuse as main transcript	c.736G>A	p.Glu246Lys	missense_variant	8/24	1	NM_001164161.2	ENSP00000377389.2		Q5H9R7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

The c.736G>A (p.E246K) alteration is located in exon 8 (coding exon 6) of the PPP6R3 gene. This alteration results from a G to A substitution at nucleotide position 736, causing the glutamic acid (E) at amino acid position 246 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;.;T;.;.;.;.;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.8

M;M;.;M;M;M;M;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.1

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0040

D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D;D;D

Polyphen

0.93

P;P;.;D;D;D;P;.

Vest4

0.86

MutPred

0.51

Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);Gain of methylation at E246 (P = 0.0087);

MVP

0.53

MPC

0.91

ClinPred

0.99

GERP RS

5.5

Varity_R

0.56

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over