NM_003620.4:c.112A>G

Variant names:

• chr17-60600526-A-G
• rs1487466505
• NM_003620.4:c.112A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003620.4(PPM1D):​c.112A>G​(p.Lys38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPM1D NM_003620.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0617733).
• BP6: Variant 17-60600526-A-G is Benign according to our data. Variant chr17-60600526-A-G is described in ClinVar as [Benign]. Clinvar id is 2877391.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1D	NM_003620.4	c.112A>G	p.Lys38Glu	missense_variant	Exon 1 of 6	ENST00000305921.8	NP_003611.1
PPM1D	XR_007065507.1	n.334A>G		non_coding_transcript_exon_variant	Exon 1 of 7
PPM1D	XR_934577.3	n.334A>G		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1D	ENST00000305921.8	c.112A>G	p.Lys38Glu	missense_variant	Exon 1 of 6	1	NM_003620.4	ENSP00000306682.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.0	.;N
REVEL	Benign	0.021
Sift	Benign	0.81	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.15
MutPred		0.27		Loss of ubiquitination at K38 (P = 8e-04);Loss of ubiquitination at K38 (P = 8e-04);
MVP		0.40
MPC		1.6
ClinPred		0.17	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.22

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

Other links and lift over

dbSNP: rs1487466505; hg19: chr17-58677887;