rs34981823

Variant names:

• chr4-88265010-C-T
• rs34981823
• NM_152542.5:c.978G>A
• PPM1K p.Val326Val

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.399
• Publications: 2 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intermediate maple syrup urine disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

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.978G>A	p.Val326Val	synonymous	Exon 6 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.978G>A	p.Val326Val	synonymous	Exon 6 of 7	ENSP00000477341.1	Q8N3J5-1
	PPM1K	ENST00000882965.1		c.978G>A	p.Val326Val	synonymous	Exon 6 of 7	ENSP00000553024.1
	PPM1K	ENST00000951960.1		c.978G>A	p.Val326Val	synonymous	Exon 7 of 8	ENSP00000622019.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3480 AN: 152136 Hom.: 132 Cov.: 33

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

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.: 31 AF XY: 0.00244 AC XY: 1776 AN XY: 727164

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: 0 AN: 39696

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000285 AC: 317 AN: 1111916

Other (OTH) AF: 0.00679 AC: 410 AN: 60386

GnomAD4 genome AF: 0.0229 AC: 3485 AN: 152254 Hom.: 132 Cov.: 33 AF XY: 0.0227 AC XY: 1689 AN XY: 74436

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: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68036

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0123 Hom.: 71

Bravo AF: 0.0262

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Maple syrup urine disease, mild variant (1)
-	-	1	not provided (1)
-	-	1	PPM1K-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.66
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34981823;

hg19: chr4-89186162;