4-88278245-G-A

Variant names:

• chr4-88278245-G-A
• rs116564150
• NM_152542.5:c.339C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_152542.5(PPM1K):​c.339C>T​(p.Phe113Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00999 in 1,614,138 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 33)
  • Exomes 𝑓: 0.010 (102 hom.)
• Consequence: PPM1K NM_152542.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.48
• Publications: 6 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-88278245-G-A is Benign according to our data. Variant chr4-88278245-G-A is described in ClinVar as Benign. ClinVar VariationId is 473874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.48 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 9 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1K	NM_152542.5	MANE Select	c.339C>T	p.Phe113Phe	synonymous	Exon 2 of 7	NP_689755.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1K	ENST00000608933.6	TSL:1 MANE Select	c.339C>T	p.Phe113Phe	synonymous	Exon 2 of 7	ENSP00000477341.1
	PPM1K	ENST00000514204.1	TSL:1	c.339C>T	p.Phe113Phe	synonymous	Exon 2 of 3	ENSP00000477241.1
	PPM1K	ENST00000506423.1	TSL:1	n.554C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1142 AN: 152174 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00769 AC: 1933 AN: 251350 AF XY: 0.00806

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.0102 AC: 14983 AN: 1461846 Hom.: 102 Cov.: 31 AF XY: 0.0101 AC XY: 7339 AN XY: 727220

African (AFR) AF: 0.00119 AC: 40 AN: 33480

American (AMR) AF: 0.00403 AC: 180 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00831 AC: 717 AN: 86254

European-Finnish (FIN) AF: 0.0145 AC: 776 AN: 53418

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0114 AC: 12650 AN: 1111982

Other (OTH) AF: 0.00960 AC: 580 AN: 60394

GnomAD4 genome AF: 0.00749 AC: 1141 AN: 152292 Hom.: 9 Cov.: 33 AF XY: 0.00766 AC XY: 570 AN XY: 74460

African (AFR) AF: 0.00180 AC: 75 AN: 41564

American (AMR) AF: 0.00582 AC: 89 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4822

European-Finnish (FIN) AF: 0.0158 AC: 168 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0110 AC: 745 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00861 Hom.: 6

Bravo AF: 0.00657

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00961

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.87
PhyloP100		-3.5
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs116564150; hg19: chr4-89199397;