4-88262618-C-A

Position:

• chr4-88262618-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152542.5(PPM1K):​c.1096G>T​(p.Ala366Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPM1K NM_152542.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

Genes affected

PPM1K (HGNC:25415): (protein phosphatase, Mg2+/Mn2+ dependent 1K) This gene encodes a member of the PPM family of Mn2+/Mg2+-dependent protein phosphatases. The encoded protein, essential for cell survival and development, is targeted to the mitochondria where it plays a key role in regulation of the mitochondrial permeability transition pore. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1K	NM_152542.5	c.1096G>T	p.Ala366Ser	missense_variant	7/7	ENST00000608933.6	NP_689755.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1K	ENST00000608933.6	c.1096G>T	p.Ala366Ser	missense_variant	7/7	1	NM_152542.5	ENSP00000477341.1
PPM1K	ENST00000295908.11	c.961G>T	p.Ala321Ser	missense_variant	6/6	5		ENSP00000295908.7
PPM1K	ENST00000508256.5	c.439G>T	p.Ala147Ser	missense_variant	6/6	2		ENSP00000476452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease, mild variant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 366 of the PPM1K protein (p.Ala366Ser). This variant has not been reported in the literature in individuals affected with PPM1K-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.044	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Uncertain	0.55	T
REVEL	Benign	0.037
Sift4G	Benign	0.41	T;T;T
Polyphen		0.31	B;.;.
Vest4		0.11
MutPred		0.33		Gain of disorder (P = 0.0348);.;.;
MVP		0.16
MPC		0.26
ClinPred		0.70	D
GERP RS		3.2
Varity_R		0.059
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-89183770;