3-52246011-C-A

Variant names:

• chr3-52246011-C-A
• rs1559446069
• NM_144641.4:c.187C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_144641.4(PPM1M):​c.187C>A​(p.Arg63Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000928 in 1,077,442 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: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: PPM1M NM_144641.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.087).
• BP7: Synonymous conserved (PhyloP=2.49 with no splicing effect.

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.187C>A	p.Arg63Arg	synonymous	Exon 1 of 10	NP_653242.3	Q96MI6-5
	PPM1M	NM_001122870.3		c.-461C>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.187C>A	p.Arg63Arg	synonymous	Exon 1 of 10	ENSP00000319894.5	Q96MI6-5
	PPM1M	ENST00000855772.1		c.187C>A	p.Arg63Arg	synonymous	Exon 1 of 10	ENSP00000525831.1
	PPM1M	ENST00000970938.1		c.187C>A	p.Arg63Arg	synonymous	Exon 1 of 10	ENSP00000640997.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077442 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 527030

⚠️ 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: 19324

American (AMR) AF: 0.00 AC: 0 AN: 18756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13686

East Asian (EAS) AF: 0.00 AC: 0 AN: 7692

South Asian (SAS) AF: 0.00 AC: 0 AN: 68566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3680

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 892920

Other (OTH) AF: 0.00 AC: 0 AN: 38678

⚠️ 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
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		2.5
PromoterAI		0.23	Neutral

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: rs1559446069; hg19: chr3-52280027;