3-52245993-C-A

Variant names:

• chr3-52245993-C-A
• rs1041261270
• NM_144641.4:c.169C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144641.4(PPM1M):​c.169C>A​(p.Pro57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign 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. P57S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: PPM1M NM_144641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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]

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]

ENSG00000306261 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36188877).

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.169C>A	p.Pro57Thr	missense	Exon 1 of 10	NP_653242.3	Q96MI6-5
	PPM1M	NM_001122870.3		c.-479C>A		upstream_gene	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.169C>A	p.Pro57Thr	missense	Exon 1 of 10	ENSP00000319894.5	Q96MI6-5
	PPM1M	ENST00000855772.1		c.169C>A	p.Pro57Thr	missense	Exon 1 of 10	ENSP00000525831.1
	PPM1M	ENST00000970938.1		c.169C>A	p.Pro57Thr	missense	Exon 1 of 10	ENSP00000640997.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091470 Hom.: 0 Cov.: 31 AF XY: 0.00000187 AC XY: 1 AN XY: 534594

⚠️ 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: 19976

American (AMR) AF: 0.0000454 AC: 1 AN: 22040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14542

East Asian (EAS) AF: 0.00 AC: 0 AN: 7812

South Asian (SAS) AF: 0.00 AC: 0 AN: 70644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3516

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 899640

Other (OTH) AF: 0.00 AC: 0 AN: 39442

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.43	T
PhyloP100		1.5
PrimateAI	Pathogenic	0.91	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.30		Gain of sheet (P = 0.0125)
MVP		0.30
ClinPred		0.35	T
GERP RS		3.3
PromoterAI		-0.021	Neutral
Mutation Taster		=85/15	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: rs1041261270; hg19: chr3-52280009;