rs16944543

Variant names:

• chr17-60600504-G-A
• rs16944543
• NM_003620.4:c.90G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-60600504-G-A
• chr17-60600504-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003620.4(PPM1D):​c.90G>A​(p.Glu30Glu) 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:4
• Conservation: PhyloP100: 2.47
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Benign. The variant received -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 VariationId 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.

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.90G>A	p.Glu30Glu	synonymous	Exon 1 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.90G>A	p.Glu30Glu	synonymous	Exon 1 of 6	ENSP00000306682.2	O15297-1
	PPM1D	ENST00000870218.1		c.90G>A	p.Glu30Glu	synonymous	Exon 1 of 6	ENSP00000540277.1
	PPM1D	ENST00000870219.1		c.90G>A	p.Glu30Glu	synonymous	Exon 1 of 4	ENSP00000540278.1

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

GnomAD2 exomes AF: 0.0112 AC: 1959 AN: 174346 AF XY: 0.00843

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 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

African (AFR) AF: 0.162 AC: 5294 AN: 32592

American (AMR) AF: 0.0110 AC: 407 AN: 37118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25268

East Asian (EAS) AF: 0.000345 AC: 13 AN: 37640

South Asian (SAS) AF: 0.000384 AC: 31 AN: 80694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50096

Middle Eastern (MID) AF: 0.00386 AC: 22 AN: 5698

European-Non Finnish (NFE) AF: 0.000206 AC: 224 AN: 1090026

Other (OTH) AF: 0.0121 AC: 710 AN: 58780

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

African (AFR) AF: 0.161 AC: 6705 AN: 41520

American (AMR) AF: 0.0203 AC: 310 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68018

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0202 Hom.: 204

Bravo AF: 0.0538

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.92
PhyloP100		2.5
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs16944543; hg19: chr17-58677865;