22-21945881-G-A

Variant names:

• chr22-21945881-G-A
• rs189969314
• NM_014634.4:c.168C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_014634.4(PPM1F):​c.168C>T​(p.Gly56Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,612,080 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PPM1F NM_014634.4 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.49

Genes affected

PPM1F (HGNC:19388): (protein phosphatase, Mg2+/Mn2+ dependent 1F) 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 can interact with Rho guanine nucleotide exchange factors (PIX), and thus block the effects of p21-activated kinase 1 (PAK), a protein kinase mediating biological effects downstream of Rho GTPases. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. The overexpression of this phosphatase or CAMK2G has been shown to mediate caspase-dependent apoptosis. An alternatively spliced transcript variant has been identified, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

PPM1F-AS1 (HGNC:40888): (PPM1F antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1F	NM_014634.4	c.168C>T	p.Gly56Gly	synonymous_variant	Exon 2 of 8	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1	c.-298-6201C>T		intron_variant	Intron 1 of 6		NP_001397765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1F	ENST00000263212.10	c.168C>T	p.Gly56Gly	synonymous_variant	Exon 2 of 8	1	NM_014634.4	ENSP00000263212.5
PPM1F-AS1	ENST00000458178.2	n.6101G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
PPM1F	ENST00000397495.8	c.168C>T	p.Gly56Gly	synonymous_variant	Exon 2 of 7	2		ENSP00000380632.4

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000221 AC: 55 AN: 249168 Hom.: 0 AF XY: 0.000237 AC XY: 32 AN XY: 134950

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1459744 Hom.: 1 Cov.: 30 AF XY: 0.000147 AC XY: 107 AN XY: 726158

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000155

EpiCase AF: 0.000327

EpiControl AF: 0.000653

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 56 of the PPM1F mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PPM1F protein. This variant is present in population databases (rs189969314, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PPM1F-related conditions. ClinVar contains an entry for this variant (Variation ID: 2054292). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs189969314; hg19: chr22-22300253; COSMIC: COSV54286821;