Genetic Variant NM_016147.3:c.47G>T (chr11-74171468-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_016147.3(PPME1):c.47G>T(p.Arg16Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,100 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPME1
NM_016147.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

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 2 ACMG points.

PM1

In a modified_residue Asymmetric dimethylarginine; alternate (size 0) in uniprot entity PPME1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25934088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	ENST00000328257.13	NP_057231.1	Q9Y570-1A0A140VK39
PPME1	NM_001271593.2 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14		NP_001258522.1	Q9Y570-4
PPME1	XM_047427116.1 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 12		XP_047283072.1
PPME1	XM_017017913.3 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPME1	ENST00000328257.13 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	1	NM_016147.3	ENSP00000329867.8	Q9Y570-1
PPME1	ENST00000398427.6 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	1		ENSP00000381461.4	Q9Y570-4
PPME1	ENST00000542710.3 link	n.202G>T		non_coding_transcript_exon_variant	Exon 1 of 4	3
PPME1	ENST00000544401.2 link	n.126G>T		non_coding_transcript_exon_variant	Exon 1 of 5	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461100

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111744

Other (OTH)

AF:

0.00

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Dec 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.47G>T (p.R16L) alteration is located in exon 1 (coding exon 1) of the PPME1 gene. This alteration results from a G to T substitution at nucleotide position 47, causing the arginine (R) at amino acid position 16 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

0.30

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.063

T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

L;L

PhyloP100

5.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.15

Sift

Benign

0.23

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.96

D;.

Vest4

0.48

MutPred

0.32

Loss of MoRF binding (P = 0.0063);Loss of MoRF binding (P = 0.0063);

MVP

0.24

MPC

0.56

ClinPred

0.96

GERP RS

5.0

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.51

Mutation Taster

=58/42

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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NM_016147.3:c.47G>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