14-60268245-A-G

Variant names:

• chr14-60268245-A-G
• rs10142834
• NM_021003.5:c.-20-14439A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000395076.9(PPM1A):​c.-20-14439A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 962,052 control chromosomes in the GnomAD database, including 78,054 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 (20380 hom., cov: 30)
  • Exomes 𝑓: 0.37 (57674 hom.)
• Consequence: PPM1A ENST00000395076.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395076.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1A	NM_021003.5	MANE Select	c.-20-14439A>G		intron	N/A	NP_066283.1
	PPM1A	NM_177952.3		c.200-14439A>G		intron	N/A	NP_808821.2
	PPM1A	NM_177951.3		c.-20-14439A>G		intron	N/A	NP_808820.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1A	ENST00000395076.9	TSL:1 MANE Select	c.-20-14439A>G		intron	N/A	ENSP00000378514.4
	PPM1A	ENST00000325658.3	TSL:1	c.-20-14439A>G		intron	N/A	ENSP00000314850.3
	PPM1A	ENST00000531143.6	TSL:1	n.200-8760A>G		intron	N/A	ENSP00000437200.2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71081 AN: 151478 Hom.: 20337 Cov.: 30

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.459

GnomAD4 exome AF: 0.369 AC: 298830 AN: 810456 Hom.: 57674 Cov.: 14 AF XY: 0.368 AC XY: 137850 AN XY: 374972

African (AFR) AF: 0.860 AC: 13147 AN: 15286

American (AMR) AF: 0.279 AC: 269 AN: 964

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 2432 AN: 5026

East Asian (EAS) AF: 0.160 AC: 560 AN: 3504

South Asian (SAS) AF: 0.474 AC: 7591 AN: 16012

European-Finnish (FIN) AF: 0.311 AC: 82 AN: 264

Middle Eastern (MID) AF: 0.434 AC: 687 AN: 1582

European-Non Finnish (NFE) AF: 0.356 AC: 263858 AN: 741280

Other (OTH) AF: 0.385 AC: 10204 AN: 26538

GnomAD4 genome AF: 0.470 AC: 71176 AN: 151596 Hom.: 20380 Cov.: 30 AF XY: 0.461 AC XY: 34122 AN XY: 74044

African (AFR) AF: 0.813 AC: 33651 AN: 41366

American (AMR) AF: 0.341 AC: 5191 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1687 AN: 3468

East Asian (EAS) AF: 0.152 AC: 785 AN: 5172

South Asian (SAS) AF: 0.467 AC: 2238 AN: 4796

European-Finnish (FIN) AF: 0.276 AC: 2884 AN: 10436

Middle Eastern (MID) AF: 0.514 AC: 150 AN: 292

European-Non Finnish (NFE) AF: 0.347 AC: 23495 AN: 67806

Other (OTH) AF: 0.454 AC: 957 AN: 2106

Alfa AF: 0.394 Hom.: 5831

Bravo AF: 0.486

Asia WGS AF: 0.320 AC: 1116 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.7
DANN	Benign	0.49
PhyloP100		-0.17
Mutation Taster		=100/0	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: rs10142834; hg19: chr14-60734963;