NM_003620.4:c.-196T>C

Variant names:

• chr17-60600219-T-C
• rs116268471
• NM_003620.4:c.-196T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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: Benign. The variant received -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 VariationId 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.

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.-196T>C		5_prime_UTR	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.-196T>C		5_prime_UTR	Exon 1 of 6	ENSP00000306682.2	O15297-1
	PPM1D	ENST00000870218.1		c.-196T>C		5_prime_UTR	Exon 1 of 6	ENSP00000540277.1
	PPM1D	ENST00000870219.1		c.-196T>C		5_prime_UTR	Exon 1 of 4	ENSP00000540278.1

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

African (AFR) AF: 0.160 AC: 3151 AN: 19704

American (AMR) AF: 0.0129 AC: 238 AN: 18414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16332

East Asian (EAS) AF: 0.000319 AC: 10 AN: 31350

South Asian (SAS) AF: 0.000427 AC: 24 AN: 56200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29446

Middle Eastern (MID) AF: 0.00466 AC: 14 AN: 3004

European-Non Finnish (NFE) AF: 0.000218 AC: 167 AN: 765030

Other (OTH) AF: 0.0124 AC: 540 AN: 43394

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

African (AFR) AF: 0.162 AC: 6729 AN: 41526

American (AMR) AF: 0.0202 AC: 309 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5146

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68012

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0443 Hom.: 59

Bravo AF: 0.0540

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.8
DANN	Benign	0.34
PhyloP100		-1.2
PromoterAI		-0.025	Neutral
Mutation Taster		=299/1	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: rs116268471; hg19: chr17-58677580;