NM_144641.4:c.398C>T

Variant names:

• chr3-52247029-C-T
• rs562720345
• NM_144641.4:c.398C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144641.4(PPM1M):​c.398C>T​(p.Ala133Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A133G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PPM1M NM_144641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• 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:):

TWF2 (HGNC:9621): (twinfilin actin binding protein 2) The protein encoded by this gene was identified by its interaction with the catalytic domain of protein kinase C-zeta. The encoded protein contains an actin-binding site and an ATP-binding site. It is most closely related to twinfilin (PTK9), a conserved actin monomer-binding protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.398C>T	p.Ala133Val	missense	Exon 3 of 10	NP_653242.3	Q96MI6-5
	PPM1M	NM_001122870.3		c.-40+217C>T		intron	N/A	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.398C>T	p.Ala133Val	missense	Exon 3 of 10	ENSP00000319894.5	Q96MI6-5
	PPM1M	ENST00000409502.7	TSL:1	c.-40+217C>T		intron	N/A	ENSP00000387046.3	Q96MI6-4
	PPM1M	ENST00000855772.1		c.398C>T	p.Ala133Val	missense	Exon 3 of 10	ENSP00000525831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690208

African (AFR) AF: 0.00 AC: 0 AN: 31652

American (AMR) AF: 0.00 AC: 0 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35786

South Asian (SAS) AF: 0.00 AC: 0 AN: 79250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079174

Other (OTH) AF: 0.00 AC: 0 AN: 58034

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0066	T
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-1.0	T
PhyloP100		6.2
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.76		Loss of disorder (P = 0.2371)
MVP		0.52
ClinPred		0.82	D
GERP RS		4.5
PromoterAI		-0.34	Neutral
Mutation Taster		=264/36	polymorphism

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: rs562720345; hg19: chr3-52281045;