Genetic Variant PPME1:p.Glu124Asp (chr11-74225230-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016147.3(PPME1):c.372A>T(p.Glu124Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PPME1
NM_016147.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

Publications

0 publications found

Variant links:

Genes affected

PPME1 (HGNC:30178): (protein phosphatase methylesterase 1) This gene encodes a protein phosphatase methylesterase localized to the nucleus. The encoded protein acts on the protein phosphatase-2A catalytic subunit and supports the ERK pathway through dephosphorylation of regulatory proteins. It plays a role in malignant glioma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

PPME1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07373911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 14	ENST00000328257.13	NP_057231.1	Q9Y570-1A0A140VK39
PPME1	NM_001271593.2 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 14		NP_001258522.1	Q9Y570-4
PPME1	XM_047427116.1 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 12		XP_047283072.1
PPME1	XM_017017913.3 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 14	1	NM_016147.3	ENSP00000329867.8		Q9Y570-1
PPME1	ENST00000398427.6 link	c.372A>T	p.Glu124Asp	missense_variant	Exon 5 of 14	1		ENSP00000381461.4		Q9Y570-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418044

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702404

African (AFR)

AF:

0.00

AC:

AN:

32272

American (AMR)

AF:

0.00

AC:

AN:

39512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25332

East Asian (EAS)

AF:

0.00

AC:

AN:

38242

South Asian (SAS)

AF:

0.00

AC:

AN:

79630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087594

Other (OTH)

AF:

0.00

AC:

AN:

58780

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.372A>T (p.E124D) alteration is located in exon 5 (coding exon 5) of the PPME1 gene. This alteration results from a A to T substitution at nucleotide position 372, causing the glutamic acid (E) at amino acid position 124 to be replaced by an aspartic acid (D). 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

0.080

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.067

T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0072

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.33

N;N

PhyloP100

1.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.53

N;N

REVEL

Benign

0.093

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.17

MutPred

0.34

Gain of ubiquitination at K119 (P = 0.2251);Gain of ubiquitination at K119 (P = 0.2251);

MVP

0.18

MPC

0.40

ClinPred

0.36

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.61

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over