rs149400522

Variant names:

• chr17-60600870-C-T
• rs149400522
• NM_003620.4:c.456C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003620.4(PPM1D):​c.456C>T​(p.Ala152Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,613,090 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (49 hom.)
• Consequence: PPM1D NM_003620.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.663
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 17-60600870-C-T is Benign according to our data. Variant chr17-60600870-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.663 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00474 (722/152378) while in subpopulation NFE AF = 0.00748 (509/68048). AF 95% confidence interval is 0.00694. There are 2 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 722 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.456C>T	p.Ala152Ala	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.456C>T	p.Ala152Ala	synonymous	Exon 1 of 6	ENSP00000306682.2	O15297-1
	PPM1D	ENST00000870218.1		c.456C>T	p.Ala152Ala	synonymous	Exon 1 of 6	ENSP00000540277.1
	PPM1D	ENST00000870219.1		c.456C>T	p.Ala152Ala	synonymous	Exon 1 of 4	ENSP00000540278.1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 722 AN: 152260 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00437 AC: 1076 AN: 246368 AF XY: 0.00459

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00334

Gnomad ASJ exome AF: 0.00692

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00494

GnomAD4 exome AF: 0.00686 AC: 10023 AN: 1460712 Hom.: 49 Cov.: 31 AF XY: 0.00665 AC XY: 4835 AN XY: 726660

African (AFR) AF: 0.00188 AC: 63 AN: 33468

American (AMR) AF: 0.00367 AC: 164 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00765 AC: 200 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86258

European-Finnish (FIN) AF: 0.00111 AC: 58 AN: 52316

Middle Eastern (MID) AF: 0.0253 AC: 146 AN: 5764

European-Non Finnish (NFE) AF: 0.00803 AC: 8925 AN: 1111982

Other (OTH) AF: 0.00636 AC: 384 AN: 60386

GnomAD4 genome AF: 0.00474 AC: 722 AN: 152378 Hom.: 2 Cov.: 33 AF XY: 0.00462 AC XY: 344 AN XY: 74510

African (AFR) AF: 0.00149 AC: 62 AN: 41594

American (AMR) AF: 0.00490 AC: 75 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00748 AC: 509 AN: 68048

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00672 Hom.: 3

Bravo AF: 0.00482

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00949

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial cancer of breast (1)
-	-	1	Familial cancer of breast;C4479517:Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (1)
-	-	1	Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.93
PhyloP100		0.66
PromoterAI		-0.0050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149400522; hg19: chr17-58678231;