3-52247719-A-G

Variant names:

• chr3-52247719-A-G
• rs989247860
• NM_144641.4:c.635A>G

Variant summary

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

The NM_144641.4(PPM1M):​c.635A>G​(p.Gln212Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,583,798 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PPM1M NM_144641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17
• Publications: 0 publications found

Genes affected

PPM1M (HGNC:26506): (protein phosphatase, Mg2+/Mn2+ dependent 1M) Predicted to enable manganese ion binding activity and phosphoprotein phosphatase activity. Predicted to be involved in protein dephosphorylation. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000306261 (HGNC:):

ACMG classification

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_144641.4. 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
	PPM1M	NM_144641.4	MANE Select	c.635A>G	p.Gln212Arg	missense	Exon 4 of 10	NP_653242.3	Q96MI6-5
	PPM1M	NM_001122870.3		c.-2A>G		5_prime_UTR	Exon 3 of 9	NP_001116342.1	Q96MI6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1M	ENST00000323588.9	TSL:1 MANE Select	c.635A>G	p.Gln212Arg	missense	Exon 4 of 10	ENSP00000319894.5	Q96MI6-5
	PPM1M	ENST00000409502.7	TSL:1	c.-2A>G		5_prime_UTR	Exon 3 of 9	ENSP00000387046.3	Q96MI6-4
	PPM1M	ENST00000855772.1		c.635A>G	p.Gln212Arg	missense	Exon 4 of 10	ENSP00000525831.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150336 Hom.: 0 Cov.: 32

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000422 AC: 1 AN: 237168 AF XY: 0.00000780

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000934

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000412 AC: 59 AN: 1433462 Hom.: 0 Cov.: 31 AF XY: 0.0000365 AC XY: 26 AN XY: 711818

African (AFR) AF: 0.00 AC: 0 AN: 32742

American (AMR) AF: 0.00 AC: 0 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 38114

South Asian (SAS) AF: 0.00 AC: 0 AN: 84538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.0000539 AC: 59 AN: 1094146

Other (OTH) AF: 0.00 AC: 0 AN: 58614

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150336 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73388

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

African (AFR) AF: 0.00 AC: 0 AN: 41134

American (AMR) AF: 0.00 AC: 0 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67480

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0091	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.96	L
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.62	T
Sift4G	Benign	0.62	T
Polyphen		0.99	D
Vest4		0.55
MVP		0.50
ClinPred		0.58	D
GERP RS		4.0
Varity_R		0.19
Mutation Taster		=81/19	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: rs989247860; hg19: chr3-52281735;