rs8011227

Positions:

• chr14-60251558-A-G
• chr14-60251558-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000395076.9(PPM1A):​c.-21+1881A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 152,110 control chromosomes in the GnomAD database, including 10,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10186 hom., cov: 32)
• Consequence: PPM1A ENST00000395076.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

Genes affected

PPM1A (HGNC:9275): (protein phosphatase, Mg2+/Mn2+ dependent 1A) 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. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1A	NM_021003.5	c.-21+1881A>G		intron_variant		ENST00000395076.9	NP_066283.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1A	ENST00000395076.9	c.-21+1881A>G		intron_variant		1	NM_021003.5	ENSP00000378514	P1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53600 AN: 151992 Hom.: 10169 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.353 AC: 53657 AN: 152110 Hom.: 10186 Cov.: 32 AF XY: 0.348 AC XY: 25845 AN XY: 74370

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.334

Alfa AF: 0.226 Hom.: 723

Bravo AF: 0.357

Asia WGS AF: 0.278 AC: 969 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Benign	0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs8011227; hg19: chr14-60718276;