4-88265017-T-C

Position:

• chr4-88265017-T-C

Variant summary

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

The NM_152542.5(PPM1K):​c.971A>G​(p.His324Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PPM1K NM_152542.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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=0.11859703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1K	NM_152542.5	c.971A>G	p.His324Arg	missense_variant	6/7	ENST00000608933.6	NP_689755.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1K	ENST00000608933.6	c.971A>G	p.His324Arg	missense_variant	6/7	1	NM_152542.5	ENSP00000477341.1
PPM1K	ENST00000508256.5	c.314A>G	p.His105Arg	missense_variant	5/6	2		ENSP00000476452.1
PPM1K	ENST00000295908.11	c.853-2291A>G		intron_variant		5		ENSP00000295908.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 05, 2019

This sequence change replaces histidine with arginine at codon 324 of the PPM1K protein (p.His324Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PPM1K-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	0.061
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N;.
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.52	T;T
Polyphen		0.028	B;.
Vest4		0.31
MutPred		0.40		Loss of disorder (P = 0.1162);.;
MVP		0.27
MPC		0.32
ClinPred		0.20	T
GERP RS		4.0
Varity_R		0.37
gMVP		0.69

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: rs1731250018; hg19: chr4-89186169;