dbSNP rs34981823: PPM1K:p.Val326Val (chr4-88265010-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_152542.5(PPM1K):c.978G>A(p.Val326Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,613,966 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 132 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 121 hom. )

Consequence

PPM1K
NM_152542.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.399

Publications

2 publications found

Variant links:

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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intermediate maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PPM1K links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-88265010-C-T is Benign according to our data. Variant chr4-88265010-C-T is described in ClinVar as Benign. ClinVar VariationId is 473876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1K	NM_152542.5 link	c.978G>A	p.Val326Val	synonymous_variant	Exon 6 of 7	ENST00000608933.6	NP_689755.3	Q8N3J5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PPM1K	ENST00000608933.6 link	c.978G>A	p.Val326Val	synonymous_variant	Exon 6 of 7	1	NM_152542.5	ENSP00000477341.1	Q8N3J5-1
PPM1K	ENST00000508256.5 link	c.321G>A	p.Val107Val	synonymous_variant	Exon 5 of 6	2		ENSP00000476452.1	V9GY69
PPM1K	ENST00000295908.11 link	c.853-2284G>A		intron_variant	Intron 5 of 5	5		ENSP00000295908.7	A0A0A0MQZ4

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3480

AN:

152136

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0777

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00983

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000411

Gnomad OTH

AF:

0.0210

GnomAD2 exomes

AF:

0.00671

AC:

1686

AN:

251288

AF XY:

0.00495

show subpopulations

Gnomad AFR exome

AF:

0.0830

Gnomad AMR exome

AF:

0.00480

Gnomad ASJ exome

AF:

0.00754

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00273

AC:

3990

AN:

1461712

Hom.:

121

Cov.:

AF XY:

0.00244

AC XY:

1776

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0826

AC:

2764

AN:

33472

American (AMR)

AF:

0.00559

AC:

250

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000186

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000285

AC:

317

AN:

1111916

Other (OTH)

AF:

0.00679

AC:

410

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

191

382

573

764

955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0229

AC:

3485

AN:

152254

Hom.:

132

Cov.:

AF XY:

0.0227

AC XY:

1689

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0776

AC:

3224

AN:

41532

American (AMR)

AF:

0.00975

AC:

149

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00951

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68036

Other (OTH)

AF:

0.0208

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

162

324

486

648

810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0262

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000764

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PPM1K-related disorder

Benign:1

Jul 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maple syrup urine disease, mild variant

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over