rs113436519

chr4-88277203-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152542.5(PPM1K):c.481A>G(p.Thr161Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000566 in 1,613,942 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: PPM1K NM_152542.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.05

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058876276).
• BP6: Variant 4-88277203-T-C is Benign according to our data. Variant chr4-88277203-T-C is described in ClinVar as [Benign]. Clinvar id is 473875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1K	NM_152542.5	c.481A>G	p.Thr161Ala	missense_variant	3/7	ENST00000608933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1K	ENST00000608933.6	c.481A>G	p.Thr161Ala	missense_variant	3/7	1	NM_152542.5	P1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000784 AC: 197 AN: 251422 Hom.: 1 AF XY: 0.000545 AC XY: 74 AN XY: 135886

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000311 AC: 455 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.000279 AC XY: 203 AN XY: 727202

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152146 Hom.: 2 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74382

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.00336

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Maple syrup urine disease, mild variant Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.037	T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.052	B;.;.
Vest4		0.25
MVP		0.41
MPC		0.26
ClinPred		0.011	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.40

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: rs113436519; hg19: chr4-89198355;