4-88265027-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152542.5(PPM1K):c.961G>A(p.Glu321Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0017 in 1,614,096 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (20 hom.)
• Consequence: PPM1K NM_152542.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.96

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00920701).
• BP6: Variant 4-88265027-C-T is Benign according to our data. Variant chr4-88265027-C-T is described in ClinVar as [Benign]. Clinvar id is 775998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00878 (1336/152216) while in subpopulation AFR AF= 0.0298 (1238/41528). AF 95% confidence interval is 0.0284. There are 21 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1K	NM_152542.5	c.961G>A	p.Glu321Lys	missense_variant	6/7	ENST00000608933.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1K	ENST00000608933.6	c.961G>A	p.Glu321Lys	missense_variant	6/7	1	NM_152542.5	P1
PPM1K	ENST00000508256.5	c.304G>A	p.Glu102Lys	missense_variant	5/6	2
PPM1K	ENST00000295908.11	c.853-2301G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00878 AC: 1335 AN: 152098 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00238 AC: 598 AN: 251408 Hom.: 12 AF XY: 0.00154 AC XY: 209 AN XY: 135884

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000960 AC: 1403 AN: 1461880 Hom.: 20 Cov.: 31 AF XY: 0.000807 AC XY: 587 AN XY: 727242

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00878 AC: 1336 AN: 152216 Hom.: 21 Cov.: 33 AF XY: 0.00836 AC XY: 622 AN XY: 74430

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00193 Hom.: 5

Bravo AF: 0.0104

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00283 AC: 344

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
Sift4G	Benign	0.079	T;T
Polyphen		0.80	P;.
Vest4		0.65
MVP		0.32
MPC		0.50
ClinPred		0.038	T
GERP RS		5.2
Varity_R		0.67
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs35523553; hg19: chr4-89186179;