11-68537797-A-T

Variant names:

• chr11-68537797-A-T
• NM_001164161.2:c.133A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164161.2(PPP6R3):​c.133A>T​(p.Ile45Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP6R3 NM_001164161.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17925942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP6R3	NM_001164161.2	c.133A>T	p.Ile45Leu	missense_variant	Exon 3 of 24	ENST00000393800.7	NP_001157633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP6R3	ENST00000393800.7	c.133A>T	p.Ile45Leu	missense_variant	Exon 3 of 24	1	NM_001164161.2	ENSP00000377389.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133A>T (p.I45L) alteration is located in exon 3 (coding exon 1) of the PPP6R3 gene. This alteration results from a A to T substitution at nucleotide position 133, causing the isoleucine (I) at amino acid position 45 to be replaced by a leucine (L). 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	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Benign	0.73
DEOGEN2	Benign	0.0059	T;T;.;T;.;.;.;.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;N;.;N;N;N;N;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.20	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.051
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.96	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030	B;.;B;.;B;B;B;B;.;.
Vest4		0.34
MutPred		0.55		Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);Loss of methylation at K43 (P = 0.0481);
MVP		0.19
MPC		0.34
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.094
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-68305265;