chr14-60258339-A-C

Position:

• chr14-60258339-A-C

Variant summary

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

The NM_021003.5(PPM1A):​c.-21+8662A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,902 control chromosomes in the GnomAD database, including 20,406 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 0.47 (20406 hom., cov: 32)
• Consequence: PPM1A NM_021003.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.188

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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1A	NM_021003.5	c.-21+8662A>C		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+8662A>C		intron_variant		1	NM_021003.5	ENSP00000378514	P1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71197 AN: 151784 Hom.: 20363 Cov.: 32

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.469 AC: 71292 AN: 151902 Hom.: 20406 Cov.: 32 AF XY: 0.461 AC XY: 34189 AN XY: 74236

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.453

Alfa AF: 0.393 Hom.: 2128

Bravo AF: 0.486

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.2
DANN	Benign	0.55

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: rs7158657; hg19: chr14-60725057;