17-60600593-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003620.4(PPM1D):​c.179G>A​(p.Gly60Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,557,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PPM1D
NM_003620.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20135498).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PPM1DNM_003620.4 linkuse as main transcriptc.179G>A p.Gly60Asp missense_variant 1/6 ENST00000305921.8
PPM1DXR_007065507.1 linkuse as main transcriptn.401G>A non_coding_transcript_exon_variant 1/7
PPM1DXR_934577.3 linkuse as main transcriptn.401G>A non_coding_transcript_exon_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PPM1DENST00000305921.8 linkuse as main transcriptc.179G>A p.Gly60Asp missense_variant 1/61 NM_003620.4 P1O15297-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000261
AC:
4
AN:
153502
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
83904
show subpopulations
Gnomad AFR exome
AF:
0.000141
Gnomad AMR exome
AF:
0.000119
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000107
AC:
15
AN:
1405146
Hom.:
0
Cov.:
31
AF XY:
0.00000576
AC XY:
4
AN XY:
694000
show subpopulations
Gnomad4 AFR exome
AF:
0.000126
Gnomad4 AMR exome
AF:
0.0000551
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000277
Gnomad4 OTH exome
AF:
0.0000859
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.00000914
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2022The c.179G>A (p.G60D) alteration is located in exon 1 (coding exon 1) of the PPM1D gene. This alteration results from a G to A substitution at nucleotide position 179, causing the glycine (G) at amino acid position 60 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 60 of the PPM1D protein (p.Gly60Asp). This variant is present in population databases (rs774135477, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PPM1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 2146371). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.18
.;T
Eigen
Benign
-0.057
Eigen_PC
Benign
-0.022
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.68
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.4
L;L
MutationTaster
Benign
0.99
D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.84
.;N
REVEL
Benign
0.13
Sift
Benign
0.34
.;T
Sift4G
Benign
0.52
T;T
Polyphen
0.90
.;P
Vest4
0.17
MutPred
0.25
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
0.62
MPC
1.5
ClinPred
0.32
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Varity_R
0.13
gMVP
0.33

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

LitVar

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

Other links and lift over

dbSNP: rs774135477; hg19: chr17-58677954; API