Variant 11-68571040-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001164161.2(PPP6R3):c.1279C>A(p.Leu427Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPP6R3
NM_001164161.2 missense, splice_region

Scores

Splicing: ADA: 0.9579

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP6R3	NM_001164161.2 linkuse as main transcript	c.1279C>A	p.Leu427Ile	missense_variant, splice_region_variant	12/24	ENST00000393800.7	NP_001157633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP6R3	ENST00000393800.7 linkuse as main transcript	c.1279C>A	p.Leu427Ile	missense_variant, splice_region_variant	12/24	1	NM_001164161.2	ENSP00000377389	P4	Q5H9R7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1411388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701444

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Dec 12, 2023

The c.1279C>A (p.L427I) alteration is located in exon 12 (coding exon 10) of the PPP6R3 gene. This alteration results from a C to A substitution at nucleotide position 1279, causing the leucine (L) at amino acid position 427 to be replaced by an isoleucine (I). 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

0.15

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.61

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

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.8

L;.;L;.;L;L;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.084

T;T;D;D;T;T;D;T;T;D

Sift4G

Benign

0.13

T;D;T;T;T;T;T;T;T;D

Polyphen

0.98

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

Vest4

0.65

MutPred

0.74

Gain of ubiquitination at K430 (P = 0.123);.;Gain of ubiquitination at K430 (P = 0.123);Gain of ubiquitination at K430 (P = 0.123);Gain of ubiquitination at K430 (P = 0.123);Gain of ubiquitination at K430 (P = 0.123);.;.;Gain of ubiquitination at K430 (P = 0.123);.;

MVP

0.32

MPC

0.55

ClinPred

0.86

GERP RS

5.4

Varity_R

0.28

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.80

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

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