17-60600219-T-C

Position:

• chr17-60600219-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003620.4(PPM1D):​c.-196T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,135,100 control chromosomes in the GnomAD database, including 903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (592 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (311 hom.)
• Consequence: PPM1D NM_003620.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-60600219-T-C is Benign according to our data. Variant chr17-60600219-T-C is described in ClinVar as [Benign]. Clinvar id is 1278802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPM1D	NM_003620.4	c.-196T>C		5_prime_UTR_variant	1/6	ENST00000305921.8
PPM1D	XR_007065507.1	n.27T>C		non_coding_transcript_exon_variant	1/7
PPM1D	XR_934577.3	n.27T>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPM1D	ENST00000305921.8	c.-196T>C		5_prime_UTR_variant	1/6	1	NM_003620.4	P1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7129 AN: 152108 Hom.: 593 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.00422 AC: 4144 AN: 982874 Hom.: 311 Cov.: 13 AF XY: 0.00369 AC XY: 1798 AN XY: 487346

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000319

Gnomad4 SAS exome AF: 0.000427

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0469 AC: 7135 AN: 152226 Hom.: 592 Cov.: 33 AF XY: 0.0447 AC XY: 3331 AN XY: 74438

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0380 Hom.: 47

Bravo AF: 0.0540

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.34

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: rs116268471; hg19: chr17-58677580;