rs568868564

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003620.4(PPM1D):c.128G>A(p.Arg43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,554,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R43G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PPM1D
NM_003620.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.70

Publications

1 publications found

Variant links:

COSMIC-nc: COSV108115222

Genes affected

PPM1D (HGNC:9277): (protein phosphatase, Mg2+/Mn2+ dependent 1D) 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. The expression of this gene is induced in a p53-dependent manner in response to various environmental stresses. While being induced by tumor suppressor protein TP53/p53, this phosphatase negatively regulates the activity of p38 MAP kinase, MAPK/p38, through which it reduces the phosphorylation of p53, and in turn suppresses p53-mediated transcription and apoptosis. This phosphatase thus mediates a feedback regulation of p38-p53 signaling that contributes to growth inhibition and the suppression of stress induced apoptosis. This gene is located in a chromosomal region known to be amplified in breast cancer. The amplification of this gene has been detected in both breast cancer cell line and primary breast tumors, which suggests a role of this gene in cancer development. [provided by RefSeq, Jul 2008]

PPM1D Gene-Disease associations (from GenCC):

intellectual developmental disorder with gastrointestinal difficulties and high pain threshold
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: Unknown, AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PPM1D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05027941).

BS2

High AC in GnomAd4 at 13 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003620.4. 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
	PPM1D	NM_003620.4	MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 1 of 6	NP_003611.1	A0A0S2Z4M2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPM1D	ENST00000305921.8	TSL:1 MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 1 of 6	ENSP00000306682.2	O15297-1
PPM1D	ENST00000870218.1		c.128G>A	p.Arg43Gln	missense	Exon 1 of 6	ENSP00000540277.1
PPM1D	ENST00000870219.1		c.128G>A	p.Arg43Gln	missense	Exon 1 of 4	ENSP00000540278.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000132

AC:

AN:

150964

AF XY:

0.000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000248

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000133

AC:

187

AN:

1402114

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

692020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31816

American (AMR)

AF:

0.000112

AC:

AN:

35852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25160

East Asian (EAS)

AF:

0.00

AC:

AN:

36098

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.000161

AC:

174

AN:

1081284

Other (OTH)

AF:

0.000138

AC:

AN:

58128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000750

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.61

REVEL

Benign

0.077

Sift

Benign

0.072

Sift4G

Benign

0.14

Polyphen

0.0020

Vest4

0.14

MVP

0.49

MPC

1.4

ClinPred

0.12

GERP RS

3.0

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.087

gMVP

0.17

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over