Genetic Variant PPM1E:p.Pro116Ser (chr17-58756343-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014906.5(PPM1E):c.346C>T(p.Pro116Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,383,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

PPM1E
NM_014906.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

Variant links:

Genes affected

PPM1E (HGNC:19322): (protein phosphatase, Mg2+/Mn2+ dependent 1E) This gene encodes a member of the PPM family of serine/threonine-protein phosphatases. The encoded protein is localized to the nucleus and dephosphorylates and inactivates multiple substrates including serine/threonine-protein kinase PAK 1, 5'-AMP-activated protein kinase (AMPK) and the multifunctional calcium/calmodulin-dependent protein kinases. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

PPM1E links:

LOC105371843 (HGNC:):

LOC105371843 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09806642).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1E	NM_014906.5 link	c.346C>T	p.Pro116Ser	missense_variant	Exon 1 of 7	ENST00000308249.4	NP_055721.3	Q8WY54-2
PPM1E	NR_048561.1 link	n.475C>T		non_coding_transcript_exon_variant	Exon 1 of 6
LOC105371843	XR_007065865.1 link	n.-238G>A		upstream_gene_variant
LOC105371843	XR_007065866.1 link	n.-233G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1E	ENST00000308249.4 link	c.346C>T	p.Pro116Ser	missense_variant	Exon 1 of 7	1	NM_014906.5	ENSP00000312411.2		Q8WY54-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000487

AC:

AN:

1231212

Hom.:

Cov.:

AF XY:

0.00000666

AC XY:

AN XY:

600504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000789

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000199

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346C>T (p.P116S) alteration is located in exon 1 (coding exon 1) of the PPM1E gene. This alteration results from a C to T substitution at nucleotide position 346, causing the proline (P) at amino acid position 116 to be replaced by a serine (S). 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

0.081

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0039

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.080

REVEL

Benign

0.042

Sift

Uncertain

0.0060

Sift4G

Benign

0.12

Vest4

0.34

MutPred

0.26

Gain of phosphorylation at P116 (P = 0.0062);

MVP

0.043

MPC

1.1

ClinPred

0.50

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.064

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over