rs747947002

Variant names:

• chr17-60656794-GAA-G
• rs747947002
• NM_003620.4:c.1215_1216delAA

Your query was ambiguous. Multiple possible variants found:

• chr17-60656794-GAA-G
• chr17-60656794-GAA-GA
• chr17-60656794-GAA-GAAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003620.4(PPM1D):​c.1215_1216delAA​(p.Glu405AspfsTer28) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPM1D NM_003620.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.30
• Publications: 4 publications found

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]

PPM1D Gene-Disease associations (from GenCC):

• intellectual developmental disorder with gastrointestinal difficulties and high pain threshold

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: Unknown, AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-60656794-GAA-G is Pathogenic according to our data. Variant chr17-60656794-GAA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 452427.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003620.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1D	NM_003620.4	MANE Select	c.1215_1216delAA	p.Glu405AspfsTer28	frameshift	Exon 5 of 6	NP_003611.1	A0A0S2Z4M2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1D	ENST00000305921.8	TSL:1 MANE Select	c.1215_1216delAA	p.Glu405AspfsTer28	frameshift	Exon 5 of 6	ENSP00000306682.2	O15297-1
	PPM1D	ENST00000870218.1		c.1068_1069delAA	p.Glu356AspfsTer28	frameshift	Exon 5 of 6	ENSP00000540277.1
	PPM1D	ENST00000870219.1		c.861_862delAA	p.Glu287AspfsTer28	frameshift	Exon 3 of 4	ENSP00000540278.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3

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

Other links and lift over

dbSNP: rs747947002; hg19: chr17-58734155;