22-21939563-GTCC-G

Variant names:

• chr22-21939563-GTCC-G
• rs749703356
• NM_014634.4:c.321_323delGGA

Variant summary

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

The NM_014634.4(PPM1F):​c.321_323delGGA​(p.Glu107del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,581,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PPM1F NM_014634.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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.321_323delGGA	p.Glu107del	disruptive_inframe_deletion	Exon 3 of 8	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1	c.-184_-182delGGA		5_prime_UTR_variant	Exon 2 of 7		NP_001397765.1
PPM1F-AS1	NR_147620.1	n.1336_1338delCTC		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.321_323delGGA	p.Glu107del	disruptive_inframe_deletion	Exon 3 of 8	1	NM_014634.4	ENSP00000263212.5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000814 AC: 16 AN: 196490 Hom.: 0 AF XY: 0.0000573 AC XY: 6 AN XY: 104786

Gnomad AFR exome AF: 0.000747

Gnomad AMR exome AF: 0.0000355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000134

Gnomad SAS exome AF: 0.0000391

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000240

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000107 AC: 153 AN: 1429656 Hom.: 0 AF XY: 0.000107 AC XY: 76 AN XY: 707968

Gnomad4 AFR exome AF: 0.000909

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.000827

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000236

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74452

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000476

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.321_323del, 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 (rs749703356, gnomAD 0.09%), 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: rs749703356; hg19: chr22-22293935;