Genetic Variant PPP1R26:p.Ala6Thr (chr9-135484526-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014811.5(PPP1R26):c.16G>A(p.Ala6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,597,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A6V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

PPP1R26
NM_014811.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1566746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R26	NM_014811.5 link	c.16G>A	p.Ala6Thr	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.16G>A	p.Ala6Thr	missense_variant	Exon 4 of 4	1	NM_014811.5	ENSP00000349274.2		Q5T8A7

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

238096

AF XY:

0.0000692

show subpopulations

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:

0.000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1445148

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

719324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32170

American (AMR)

AF:

0.0000252

AC:

AN:

39638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.000202

AC:

AN:

39562

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4290

European-Non Finnish (NFE)

AF:

0.0000723

AC:

AN:

1107170

Other (OTH)

AF:

0.0000168

AC:

AN:

59378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.16G>A (p.A6T) alteration is located in exon 4 (coding exon 1) of the PPP1R26 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). 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

0.086

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

T;T;T;T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

.;.;.;.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

M;M;M;M;M

PhyloP100

5.2

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.3

.;.;D;D;.

REVEL

Benign

0.16

Sift

Uncertain

0.0070

.;.;D;D;.

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

1.0

D;D;D;D;D

Vest4

0.070

MVP

0.093

MPC

0.15

ClinPred

0.25

GERP RS

3.6

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.15

gMVP

0.39

Mutation Taster

=85/15

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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9-135484526-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over