dbSNP rs749371622: PPM1F:p.Thr321Ile (chr22-21925592-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014634.4(PPM1F):c.962C>T(p.Thr321Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T321T) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

PPM1F
NM_014634.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.68

Publications

0 publications found

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014634.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1F	NM_014634.4	MANE Select	c.962C>T	p.Thr321Ile	missense	Exon 7 of 8	NP_055449.1	P49593-1
	PPM1F	NM_001410836.1		c.458C>T	p.Thr153Ile	missense	Exon 6 of 7	NP_001397765.1	B5MCT7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPM1F	ENST00000263212.10	TSL:1 MANE Select	c.962C>T	p.Thr321Ile	missense	Exon 7 of 8	ENSP00000263212.5	P49593-1
PPM1F	ENST00000397495.8	TSL:2	c.962C>T	p.Thr321Ile	missense	Exon 7 of 7	ENSP00000380632.4	A8MX49
PPM1F	ENST00000407142.5	TSL:5	c.458C>T	p.Thr153Ile	missense	Exon 5 of 6	ENSP00000384930.1	B5MCT7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250978

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.042

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

M_CAP

Benign

0.0073

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.45

PhyloP100

3.7

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.17

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

0.20

Vest4

0.68

MutPred

0.59

Loss of sheet (P = 0.0817)

MVP

0.51

MPC

1.3

ClinPred

0.93

GERP RS

5.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.64

gMVP

0.77

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over