17-60600545-C-G

Position:

• chr17-60600545-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003620.4(PPM1D):​c.131C>G​(p.Ser44Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,553,936 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: PPM1D NM_003620.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.40

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07827225).
• BP6: Variant 17-60600545-C-G is Benign according to our data. Variant chr17-60600545-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1049549.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1D	NM_003620.4	c.131C>G	p.Ser44Trp	missense_variant	1/6	ENST00000305921.8
PPM1D	XR_007065507.1	n.353C>G		non_coding_transcript_exon_variant	1/7
PPM1D	XR_934577.3	n.353C>G		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1D	ENST00000305921.8	c.131C>G	p.Ser44Trp	missense_variant	1/6	1	NM_003620.4	P1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000260 AC: 39 AN: 150276 Hom.: 0 AF XY: 0.000271 AC XY: 22 AN XY: 81032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.000120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000590

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000405 AC: 567 AN: 1401658 Hom.: 2 Cov.: 31 AF XY: 0.000405 AC XY: 280 AN XY: 691776

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000495

Gnomad4 NFE exome AF: 0.000482

Gnomad4 OTH exome AF: 0.000327

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000468 Hom.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000123 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2023	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 44 of the PPM1D protein (p.Ser44Trp). This variant is present in population databases (rs373862041, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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: 1049549). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PPM1D p.S44W variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs373862041) and in control databases in 55 of 181610 chromosomes at a frequency of 0.0003028, and was observed at the highest allele count in the European (non-Finnish) population in 39 of 71508 chromosomes (freq: 0.0005454) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S44 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PPM1D: PP2, BS1 -

Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.13
Sift	Uncertain	0.013	.;D
Sift4G	Uncertain	0.050	T;D
Polyphen		0.95	.;P
Vest4		0.40
MVP		0.59
MPC		2.0
ClinPred		0.19	T
GERP RS		4.1
Varity_R		0.19
gMVP		0.25

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: rs373862041; hg19: chr17-58677906; COSMIC: COSV59958841; COSMIC: COSV59958841;