17-58756397-C-A

Position:

• chr17-58756397-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014906.5(PPM1E):​c.400C>A​(p.Arg134Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,210,214 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: 0.0000066 (0 hom.)
• Consequence: PPM1E NM_014906.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13845512).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1E	NM_014906.5	c.400C>A	p.Arg134Ser	missense_variant	1/7	ENST00000308249.4	NP_055721.3
PPM1E	NR_048561.1	n.529C>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1E	ENST00000308249.4	c.400C>A	p.Arg134Ser	missense_variant	1/7	1	NM_014906.5	ENSP00000312411	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000661 AC: 8 AN: 1210214 Hom.: 0 Cov.: 33 AF XY: 0.00000680 AC XY: 4 AN XY: 587974

Gnomad4 AFR exome AF: 0.0000423

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000705

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.400C>A (p.R134S) alteration is located in exon 1 (coding exon 1) of the PPM1E gene. This alteration results from a C to A substitution at nucleotide position 400, causing the arginine (R) at amino acid position 134 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.090
Sift	Benign	0.068	T
Sift4G	Benign	0.72	T
Vest4		0.40
MutPred		0.31		Gain of phosphorylation at R134 (P = 0.0096);
MVP		0.043
MPC		1.6
ClinPred		0.42	T
GERP RS		1.4
Varity_R		0.14
gMVP		0.15

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

Other links and lift over

dbSNP: rs1052458788; hg19: chr17-56833758;