NM_014634.4:c.969C>A

Variant names:

• chr22-21925585-G-T
• rs60327076
• NM_014634.4:c.969C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014634.4(PPM1F):​c.969C>A​(p.Ala323Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,613,726 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (58 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (51 hom.)
• Consequence: PPM1F NM_014634.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 22-21925585-G-T is Benign according to our data. Variant chr22-21925585-G-T is described in ClinVar as Benign. ClinVar VariationId is 769152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0537 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.969C>A	p.Ala323Ala	synonymous	Exon 7 of 8	NP_055449.1	P49593-1
	PPM1F	NM_001410836.1		c.465C>A	p.Ala155Ala	synonymous	Exon 6 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.969C>A	p.Ala323Ala	synonymous	Exon 7 of 8	ENSP00000263212.5	P49593-1
	PPM1F	ENST00000397495.8	TSL:2	c.969C>A	p.Ala323Ala	synonymous	Exon 7 of 7	ENSP00000380632.4	A8MX49
	PPM1F	ENST00000407142.5	TSL:5	c.465C>A	p.Ala155Ala	synonymous	Exon 5 of 6	ENSP00000384930.1	B5MCT7

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2435 AN: 152192 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00422 AC: 1058 AN: 250998 AF XY: 0.00302

Gnomad AFR exome AF: 0.0563

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00175 AC: 2562 AN: 1461416 Hom.: 51 Cov.: 30 AF XY: 0.00145 AC XY: 1051 AN XY: 727000

African (AFR) AF: 0.0611 AC: 2044 AN: 33472

American (AMR) AF: 0.00369 AC: 165 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.0000926 AC: 103 AN: 1111732

Other (OTH) AF: 0.00364 AC: 220 AN: 60372

GnomAD4 genome AF: 0.0160 AC: 2437 AN: 152310 Hom.: 58 Cov.: 33 AF XY: 0.0157 AC XY: 1171 AN XY: 74480

African (AFR) AF: 0.0556 AC: 2310 AN: 41560

American (AMR) AF: 0.00556 AC: 85 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68036

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00212 Hom.: 2

Bravo AF: 0.0186

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.37
DANN	Benign	0.61
PhyloP100		-1.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs60327076; hg19: chr22-22279958;