17-60600504-G-A

Position:

• chr17-60600504-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003620.4(PPM1D):​c.90G>A​(p.Glu30=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.47

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1D	NM_003620.4	c.90G>A	p.Glu30=	synonymous_variant	1/6	ENST00000305921.8	NP_003611.1
PPM1D	XR_007065507.1	n.312G>A		non_coding_transcript_exon_variant	1/7
PPM1D	XR_934577.3	n.312G>A		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1D	ENST00000305921.8	c.90G>A	p.Glu30=	synonymous_variant	1/6	1	NM_003620.4	ENSP00000306682	P1

Frequencies

GnomAD3 genomes AF: 0.0467 AC: 7107 AN: 152130 Hom.: 588 Cov.: 33

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

GnomAD3 exomes AF: 0.0112 AC: 1959 AN: 174346 Hom.: 131 AF XY: 0.00843 AC XY: 789 AN XY: 93594

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 SAS exome AF: 0.000249

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.: 31 AF XY: 0.00403 AC XY: 2823 AN XY: 701162

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000345

Gnomad4 SAS exome AF: 0.000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0467 AC: 7111 AN: 152246 Hom.: 587 Cov.: 33 AF XY: 0.0447 AC XY: 3325 AN XY: 74444

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0177 Hom.: 117

Bravo AF: 0.0538

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs16944543; hg19: chr17-58677865;