rs2070507

Variant names:

• chr22-21923198-A-C
• rs2070507
• NM_014634.4:c.1259T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-21923198-A-C
• chr22-21923198-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014634.4(PPM1F):​c.1259T>G​(p.Leu420Arg) variant causes a missense change. The variant allele was found at a frequency of 0.054 in 1,613,368 control chromosomes in the GnomAD database, including 4,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (323 hom., cov: 31)
  • Exomes 𝑓: 0.055 (3954 hom.)
• Consequence: PPM1F NM_014634.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016982555).
• BP6: Variant 22-21923198-A-C is Benign according to our data. Variant chr22-21923198-A-C is described in ClinVar as Benign. ClinVar VariationId is 2035947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

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.1259T>G	p.Leu420Arg	missense	Exon 8 of 8	NP_055449.1	P49593-1
	PPM1F	NM_001410836.1		c.755T>G	p.Leu252Arg	missense	Exon 7 of 7	NP_001397765.1	B5MCT7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1F	ENST00000263212.10	TSL:1 MANE Select	c.1259T>G	p.Leu420Arg	missense	Exon 8 of 8	ENSP00000263212.5	P49593-1
	PPM1F	ENST00000407142.5	TSL:5	c.755T>G	p.Leu252Arg	missense	Exon 6 of 6	ENSP00000384930.1	B5MCT7
	PPM1F	ENST00000496143.5	TSL:4	n.471T>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6493 AN: 151864 Hom.: 323 Cov.: 31

Gnomad AFR AF: 0.00928

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0420

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0680 AC: 16971 AN: 249752 AF XY: 0.0721

Gnomad AFR exome AF: 0.00958

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0452

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0551 AC: 80590 AN: 1461386 Hom.: 3954 Cov.: 32 AF XY: 0.0578 AC XY: 42032 AN XY: 727006

African (AFR) AF: 0.00759 AC: 254 AN: 33478

American (AMR) AF: 0.0340 AC: 1519 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 536 AN: 26128

East Asian (EAS) AF: 0.248 AC: 9853 AN: 39696

South Asian (SAS) AF: 0.164 AC: 14158 AN: 86238

European-Finnish (FIN) AF: 0.0517 AC: 2739 AN: 53024

Middle Eastern (MID) AF: 0.0274 AC: 158 AN: 5768

European-Non Finnish (NFE) AF: 0.0429 AC: 47731 AN: 1111950

Other (OTH) AF: 0.0603 AC: 3642 AN: 60388

GnomAD4 genome AF: 0.0427 AC: 6493 AN: 151982 Hom.: 323 Cov.: 31 AF XY: 0.0472 AC XY: 3508 AN XY: 74274

African (AFR) AF: 0.00926 AC: 384 AN: 41486

American (AMR) AF: 0.0385 AC: 588 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3466

East Asian (EAS) AF: 0.223 AC: 1147 AN: 5138

South Asian (SAS) AF: 0.184 AC: 879 AN: 4786

European-Finnish (FIN) AF: 0.0442 AC: 468 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0420 AC: 2850 AN: 67916

Other (OTH) AF: 0.0332 AC: 70 AN: 2110

Alfa AF: 0.0468 Hom.: 1006

Bravo AF: 0.0373

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0439 AC: 169

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0403 AC: 347

ExAC AF: 0.0705 AC: 8561

Asia WGS AF: 0.214 AC: 741 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.21
MPC		1.4
ClinPred		0.032	T
GERP RS		5.3
Varity_R		0.47
gMVP		0.91
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070507; hg19: chr22-22277571; COSMIC: COSV54285603; COSMIC: COSV54285603;