17-60600504-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003620.4(PPM1D):c.90G>A(p.Glu30Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,570,158 control chromosomes in the GnomAD database, including 1,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 587 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 471 hom. )

Consequence

PPM1D
NM_003620.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.47

Publications

4 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 17-60600504-G-A is Benign according to our data. Variant chr17-60600504-G-A is described in ClinVar as Benign. ClinVar VariationId is 1277034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.47 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

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.90G>A	p.Glu30Glu	synonymous	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.90G>A	p.Glu30Glu	synonymous	Exon 1 of 6	ENSP00000306682.2	O15297-1
PPM1D	ENST00000870218.1		c.90G>A	p.Glu30Glu	synonymous	Exon 1 of 6	ENSP00000540277.1
PPM1D	ENST00000870219.1		c.90G>A	p.Glu30Glu	synonymous	Exon 1 of 4	ENSP00000540278.1

Frequencies

GnomAD3 genomes

AF:

0.0467

AC:

7107

AN:

152130

Hom.:

588

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0112

AC:

1959

AN:

174346

AF XY:

0.00843

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.00915

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000603

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000379

Gnomad OTH exome

AF:

0.00546

GnomAD4 exome

AF:

0.00473

AC:

6701

AN:

1417912

Hom.:

471

Cov.:

AF XY:

0.00403

AC XY:

2823

AN XY:

701162

show subpopulations

African (AFR)

AF:

0.162

AC:

5294

AN:

32592

American (AMR)

AF:

0.0110

AC:

407

AN:

37118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25268

East Asian (EAS)

AF:

0.000345

AC:

AN:

37640

South Asian (SAS)

AF:

0.000384

AC:

AN:

80694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50096

Middle Eastern (MID)

AF:

0.00386

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000206

AC:

224

AN:

1090026

Other (OTH)

AF:

0.0121

AC:

710

AN:

58780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

373

746

1120

1493

1866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.0467

AC:

7111

AN:

152246

Hom.:

587

Cov.:

AF XY:

0.0447

AC XY:

3325

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.161

AC:

6705

AN:

41520

American (AMR)

AF:

0.0203

AC:

310

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68018

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

307

614

922

1229

1536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0202

Hom.:

204

Bravo

AF:

0.0538

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

9.8

(source)

DANN

Benign

0.92

PhyloP100

2.5

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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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