4-88282518-A-G

Variant names:

• chr4-88282518-A-G
• rs893971
• NM_152542.5:c.-60+1888T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152542.5(PPM1K):​c.-60+1888T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,154 control chromosomes in the GnomAD database, including 8,702 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8702 hom., cov: 33)
• Consequence: PPM1K NM_152542.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.451
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1K	NM_152542.5	c.-60+1888T>C		intron_variant	Intron 1 of 6	ENST00000608933.6	NP_689755.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1K	ENST00000608933.6	c.-60+1888T>C		intron_variant	Intron 1 of 6	1	NM_152542.5	ENSP00000477341.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48857 AN: 152036 Hom.: 8700 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.334

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.321 AC: 48872 AN: 152154 Hom.: 8702 Cov.: 33 AF XY: 0.316 AC XY: 23512 AN XY: 74382

African (AFR) AF: 0.219 AC: 9073 AN: 41516

American (AMR) AF: 0.286 AC: 4365 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1556 AN: 3466

East Asian (EAS) AF: 0.0146 AC: 76 AN: 5192

South Asian (SAS) AF: 0.263 AC: 1269 AN: 4820

European-Finnish (FIN) AF: 0.362 AC: 3830 AN: 10568

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.405 AC: 27503 AN: 67988

Other (OTH) AF: 0.332 AC: 702 AN: 2114

Alfa AF: 0.370 Hom.: 19876

Bravo AF: 0.308

Asia WGS AF: 0.137 AC: 478 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.6
DANN	Benign	0.55
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs893971; hg19: chr4-89203670;