22-21939572-CTCT-C

Variant names:

• chr22-21939572-CTCT-C
• rs764578206
• NM_014634.4:c.312_314delAGA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_014634.4(PPM1F):​c.312_314delAGA​(p.Glu105del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,577,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: PPM1F NM_014634.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_014634.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1F	NM_014634.4	c.312_314delAGA	p.Glu105del	disruptive_inframe_deletion	Exon 3 of 8	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1	c.-193_-191delAGA		5_prime_UTR_variant	Exon 2 of 7		NP_001397765.1
PPM1F-AS1	NR_147620.1	n.1345_1347delTTC		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1F	ENST00000263212.10	c.312_314delAGA	p.Glu105del	disruptive_inframe_deletion	Exon 3 of 8	1	NM_014634.4	ENSP00000263212.5

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000475 AC: 91 AN: 191762 Hom.: 0 AF XY: 0.000577 AC XY: 59 AN XY: 102186

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000317

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.000632

Gnomad OTH exome AF: 0.000585

GnomAD4 exome AF: 0.000589 AC: 840 AN: 1425536 Hom.: 0 AF XY: 0.000600 AC XY: 423 AN XY: 705570

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000310

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000416

Gnomad4 FIN exome AF: 0.000744

Gnomad4 NFE exome AF: 0.000662

Gnomad4 OTH exome AF: 0.000406

GnomAD4 genome AF: 0.000505 AC: 77 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74488

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.000461

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.312_314del, results in the deletion of 1 amino acid(s) of the PPM1F protein (p.Glu107del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs764578206, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PPM1F-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

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: rs764578206; hg19: chr22-22293944;