Variant 22-21923198-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_014634.4(PPM1F):c.1259T>G(p.Leu420Arg) variant causes a missense change. The variant allele was found at a frequency of 0.054 in 1,613,368 control chromosomes in the GnomAD database, including 4,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.043 ( 323 hom., cov: 31)

Exomes 𝑓: 0.055 ( 3954 hom. )

Consequence

PPM1F
NM_014634.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.71

Variant links:

Genes affected

PPM1F (HGNC:19388): (protein phosphatase, Mg2+/Mn2+ dependent 1F) The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase can interact with Rho guanine nucleotide exchange factors (PIX), and thus block the effects of p21-activated kinase 1 (PAK), a protein kinase mediating biological effects downstream of Rho GTPases. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. The overexpression of this phosphatase or CAMK2G has been shown to mediate caspase-dependent apoptosis. An alternatively spliced transcript variant has been identified, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

PPM1F links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016982555).

BP6

Variant 22-21923198-A-C is Benign according to our data. Variant chr22-21923198-A-C is described in ClinVar as [Benign]. Clinvar id is 2035947.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1F	NM_014634.4 linkuse as main transcript	c.1259T>G	p.Leu420Arg	missense_variant	8/8	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1 linkuse as main transcript	c.755T>G	p.Leu252Arg	missense_variant	7/7		NP_001397765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1F	ENST00000263212.10 linkuse as main transcript	c.1259T>G	p.Leu420Arg	missense_variant	8/8	1	NM_014634.4	ENSP00000263212	P1	P49593-1
PPM1F	ENST00000407142.5 linkuse as main transcript	c.755T>G	p.Leu252Arg	missense_variant	6/6	5		ENSP00000384930
PPM1F	ENST00000496143.5 linkuse as main transcript	n.471T>G		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes

AF:

0.0428

AC:

6493

AN:

151864

Hom.:

323

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00928

Gnomad AMI

AF:

0.0396

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0185

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.0442

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0420

Gnomad OTH

AF:

0.0326

GnomAD3 exomes

AF:

0.0680

AC:

16971

AN:

249752

Hom.:

1095

AF XY:

0.0721

AC XY:

9745

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00958

Gnomad AMR exome

AF:

0.0340

Gnomad ASJ exome

AF:

0.0223

Gnomad EAS exome

AF:

0.207

Gnomad SAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.0488

Gnomad NFE exome

AF:

0.0452

Gnomad OTH exome

AF:

0.0505

GnomAD4 exome

AF:

0.0551

AC:

80590

AN:

1461386

Hom.:

3954

Cov.:

AF XY:

0.0578

AC XY:

42032

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00759

Gnomad4 AMR exome

AF:

0.0340

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.248

Gnomad4 SAS exome

AF:

0.164

Gnomad4 FIN exome

AF:

0.0517

Gnomad4 NFE exome

AF:

0.0429

Gnomad4 OTH exome

AF:

0.0603

GnomAD4 genome

AF:

0.0427

AC:

6493

AN:

151982

Hom.:

323

Cov.:

AF XY:

0.0472

AC XY:

3508

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00926

Gnomad4 AMR

AF:

0.0385

Gnomad4 ASJ

AF:

0.0185

Gnomad4 EAS

AF:

0.223

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.0442

Gnomad4 NFE

AF:

0.0420

Gnomad4 OTH

AF:

0.0332

Alfa

AF:

0.0450

Hom.:

450

Bravo

AF:

0.0373

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0439

AC:

169

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.0403

AC:

347

ExAC

AF:

0.0705

AC:

8561

Asia WGS

AF:

0.214

AC:

741

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.000099

P;P;P

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

0.99

D;.

Vest4

0.21

MPC

1.4

ClinPred

0.032

GERP RS

5.3

Varity_R

0.47

gMVP

0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over