chr17-60600574-T-G

Position:

• chr17-60600574-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003620.4(PPM1D):​c.160T>G​(p.Ser54Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPM1D NM_003620.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.265

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08771077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1D	NM_003620.4	c.160T>G	p.Ser54Ala	missense_variant	1/6	ENST00000305921.8
PPM1D	XR_007065507.1	n.382T>G		non_coding_transcript_exon_variant	1/7
PPM1D	XR_934577.3	n.382T>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1D	ENST00000305921.8	c.160T>G	p.Ser54Ala	missense_variant	1/6	1	NM_003620.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

The c.160T>G (p.S54A) alteration is located in exon 1 (coding exon 1) of the PPM1D gene. This alteration results from a T to G substitution at nucleotide position 160, causing the serine (S) at amino acid position 54 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.5
DANN	Benign	0.90
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.19	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.68	.;N
REVEL	Benign	0.052
Sift	Benign	0.32	.;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0	.;B
Vest4		0.14
MutPred		0.26		Loss of phosphorylation at S54 (P = 0.0017);Loss of phosphorylation at S54 (P = 0.0017);
MVP		0.32
MPC		0.99
ClinPred		0.11	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.071
gMVP		0.085

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-58677935;