rs137892679

Variant names:

• chr22-21939600-C-A
• rs137892679
• NM_014634.4:c.287G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-21939600-C-A
• chr22-21939600-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001410836.1(PPM1F):​c.-218G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PPM1F NM_001410836.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.216
• Publications: 0 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]

PPM1F-AS1 (HGNC:40888): (PPM1F antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14155695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410836.1. 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.287G>T	p.Arg96Met	missense	Exon 3 of 8	NP_055449.1	P49593-1
	PPM1F	NM_001410836.1		c.-218G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001397765.1	B5MCT7
	PPM1F	NM_001410836.1		c.-218G>T		5_prime_UTR	Exon 2 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.287G>T	p.Arg96Met	missense	Exon 3 of 8	ENSP00000263212.5	P49593-1
	PPM1F-AS1	ENST00000458178.2	TSL:1	n.1308C>A		non_coding_transcript_exon	Exon 1 of 2
	PPM1F	ENST00000445205.1	TSL:5	c.-218G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000392372.1	C9J2F3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413992 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698736

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32514

American (AMR) AF: 0.00 AC: 0 AN: 36976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 80630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086128

Other (OTH) AF: 0.0000170 AC: 1 AN: 58690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.22
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.093
Sift	Uncertain	0.021	D
Sift4G	Benign	0.074	T
Polyphen		0.74	P
Vest4		0.41
MutPred		0.17		Loss of methylation at K97 (P = 0.0286)
MVP		0.42
MPC		0.85
ClinPred		0.89	D
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.25
Mutation Taster		=95/5	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: rs137892679; hg19: chr22-22293972;