17-60600545-C-T

Variant names:

• chr17-60600545-C-T
• rs373862041
• NM_003620.4:c.131C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003620.4(PPM1D):​c.131C>T​(p.Ser44Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000428 in 1,401,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S44W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PPM1D NM_003620.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11316824).
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

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.131C>T	p.Ser44Leu	missense	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.131C>T	p.Ser44Leu	missense	Exon 1 of 6	ENSP00000306682.2	O15297-1
	PPM1D	ENST00000870218.1		c.131C>T	p.Ser44Leu	missense	Exon 1 of 6	ENSP00000540277.1
	PPM1D	ENST00000870219.1		c.131C>T	p.Ser44Leu	missense	Exon 1 of 4	ENSP00000540278.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000665 AC: 1 AN: 150276 AF XY: 0.0000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1401658 Hom.: 0 Cov.: 31 AF XY: 0.00000578 AC XY: 4 AN XY: 691776

African (AFR) AF: 0.00 AC: 0 AN: 31782

American (AMR) AF: 0.00 AC: 0 AN: 35832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 36054

South Asian (SAS) AF: 0.00 AC: 0 AN: 79466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00000555 AC: 6 AN: 1081100

Other (OTH) AF: 0.00 AC: 0 AN: 58110

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.046
Sift	Benign	0.21	T
Sift4G	Benign	0.40	T
Polyphen		0.048	B
Vest4		0.16
MutPred		0.33		Loss of phosphorylation at S44 (P = 0.0013)
MVP		0.44
MPC		1.1
ClinPred		0.50	D
GERP RS		4.1
PromoterAI		0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.19
Mutation Taster		=85/15	polymorphism

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: rs373862041; hg19: chr17-58677906;