22-21923112-G-C

Position:

• chr22-21923112-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014634.4(PPM1F):​c.1345C>G​(p.Gln449Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,608,658 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (28 hom., cov: 31)
  • Exomes 𝑓: 0.00096 (16 hom.)
• Consequence: PPM1F NM_014634.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.88

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024405718).
• BP6: Variant 22-21923112-G-C is Benign according to our data. Variant chr22-21923112-G-C is described in ClinVar as [Benign]. Clinvar id is 2047621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00842 (1282/152264) while in subpopulation AFR AF= 0.0293 (1218/41538). AF 95% confidence interval is 0.028. There are 28 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1F	NM_014634.4	c.1345C>G	p.Gln449Glu	missense_variant	8/8	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1	c.841C>G	p.Gln281Glu	missense_variant	7/7		NP_001397765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1F	ENST00000263212.10	c.1345C>G	p.Gln449Glu	missense_variant	8/8	1	NM_014634.4	ENSP00000263212	P1
PPM1F	ENST00000407142.5	c.841C>G	p.Gln281Glu	missense_variant	6/6	5		ENSP00000384930
PPM1F	ENST00000496143.5			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1274 AN: 152146 Hom.: 28 Cov.: 31

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00235 AC: 580 AN: 246982 Hom.: 8 AF XY: 0.00157 AC XY: 210 AN XY: 133784

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000955 AC: 1391 AN: 1456394 Hom.: 16 Cov.: 31 AF XY: 0.000824 AC XY: 597 AN XY: 724358

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000829

Gnomad4 OTH exome AF: 0.00196

GnomAD4 genome AF: 0.00842 AC: 1282 AN: 152264 Hom.: 28 Cov.: 31 AF XY: 0.00802 AC XY: 597 AN XY: 74442

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00264 Hom.: 2

Bravo AF: 0.00953

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.015
DANN	Benign	0.52
DEOGEN2	Benign	0.040	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.015
Sift	Benign	0.42	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.0010	B;.
Vest4		0.029
MVP		0.24
MPC		0.44
ClinPred		0.0038	T
GERP RS		-9.4
Varity_R		0.031
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74525416; hg19: chr22-22277485;