4-88262618-C-A

Variant names:

• chr4-88262618-C-A
• NM_152542.5:c.1096G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/20 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
• Publications: 0 publications found

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]

PPM1K Gene-Disease associations (from GenCC):

• maple syrup urine disease, mild variant

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152542.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1K	NM_152542.5	MANE Select	c.1096G>T	p.Ala366Ser	missense	Exon 7 of 7	NP_689755.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1K	ENST00000608933.6	TSL:1 MANE Select	c.1096G>T	p.Ala366Ser	missense	Exon 7 of 7	ENSP00000477341.1	Q8N3J5-1
	PPM1K	ENST00000882965.1		c.1096G>T	p.Ala366Ser	missense	Exon 7 of 7	ENSP00000553024.1
	PPM1K	ENST00000951960.1		c.1096G>T	p.Ala366Ser	missense	Exon 8 of 8	ENSP00000622019.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Maple syrup urine disease, mild variant (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.7
PrimateAI	Uncertain	0.55	T
REVEL	Benign	0.037
Sift4G	Benign	0.41	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
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

hg19: chr4-89183770;