Genetic Variant PPP1R26:p.Val47Leu (chr9-135484649-G-T) – 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_014811.5(PPP1R26):c.139G>T(p.Val47Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,008 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 1 hom. )

Consequence

PPP1R26
NM_014811.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23

Publications

0 publications found

Variant links:

Genes affected

PPP1R26 (HGNC:29089): (protein phosphatase 1 regulatory subunit 26) Predicted to enable protein phosphatase inhibitor activity. Predicted to be involved in negative regulation of phosphatase activity. Predicted to be located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

PPP1R26 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R26	NM_014811.5 link	c.139G>T	p.Val47Leu	missense_variant	Exon 4 of 4	ENST00000356818.7	NP_055626.3	Q5T8A7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R26	ENST00000356818.7 link	c.139G>T	p.Val47Leu	missense_variant	Exon 4 of 4	1	NM_014811.5	ENSP00000349274.2		Q5T8A7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459008

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725850

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111944

Other (OTH)

AF:

0.00

AC:

AN:

60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Apr 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.139G>T (p.V47L) alteration is located in exon 4 (coding exon 1) of the PPP1R26 gene. This alteration results from a G to T substitution at nucleotide position 139, causing the valine (V) at amino acid position 47 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

Pathogenic

0.76

BayesDel_addAF

Benign

0.0034

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T;T;T;T

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;.;.;.;T

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.53

D;D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.7

M;M;M;M;M

PhyloP100

7.2

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.8

.;.;D;D;.

REVEL

Benign

0.22

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Uncertain

0.025

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.58

MutPred

0.23

Gain of catalytic residue at M49 (P = 0.0245);Gain of catalytic residue at M49 (P = 0.0245);Gain of catalytic residue at M49 (P = 0.0245);Gain of catalytic residue at M49 (P = 0.0245);Gain of catalytic residue at M49 (P = 0.0245);

MVP

0.27

MPC

0.16

ClinPred

0.96

GERP RS

5.4

PromoterAI

0.014

Neutral

(source)

Varity_R

0.60

gMVP

0.74

Mutation Taster

=86/14

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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9-135484649-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over