22-21945862-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014634.4(PPM1F):ā€‹c.187A>Gā€‹(p.Met63Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

PPM1F
NM_014634.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:1

Conservation

PhyloP100: -1.34
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04949385).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PPM1FNM_014634.4 linkc.187A>G p.Met63Val missense_variant 2/8 ENST00000263212.10 NP_055449.1 P49593-1
PPM1FNM_001410836.1 linkc.-298-6182A>G intron_variant NP_001397765.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPM1FENST00000263212.10 linkc.187A>G p.Met63Val missense_variant 2/81 NM_014634.4 ENSP00000263212.5 P49593-1
PPM1F-AS1ENST00000458178.2 linkn.6082T>C non_coding_transcript_exon_variant 2/21
PPM1FENST00000397495.8 linkc.187A>G p.Met63Val missense_variant 2/72 ENSP00000380632.4 A8MX49

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248348
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134566
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000894
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1458746
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
725726
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152308
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000284
Hom.:
0
Bravo
AF:
0.0000151
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 14, 2023The c.187A>G (p.M63V) alteration is located in exon 2 (coding exon 1) of the PPM1F gene. This alteration results from a A to G substitution at nucleotide position 187, causing the methionine (M) at amino acid position 63 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
1.6
DANN
Benign
0.92
DEOGEN2
Benign
0.071
T;T
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.97
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.58
T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.049
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.7
L;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.024
Sift
Benign
0.040
D;D
Sift4G
Uncertain
0.022
D;D
Polyphen
0.0
B;B
Vest4
0.10
MutPred
0.32
Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP
0.21
MPC
0.41
ClinPred
0.022
T
GERP RS
-2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.10
gMVP
0.24

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376410604; hg19: chr22-22300234; API