11-74204444-C-T

Variant names:

• chr11-74204444-C-T
• rs79972734
• NM_016147.3:c.287C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016147.3(PPME1):​c.287C>T​(p.Thr96Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000687 in 1,455,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PPME1 NM_016147.3 missense, splice_region
• Scores: Splicing: ADA: 0.9947
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37
• Publications: 3 publications found

Genes affected

PPME1 (HGNC:30178): (protein phosphatase methylesterase 1) This gene encodes a protein phosphatase methylesterase localized to the nucleus. The encoded protein acts on the protein phosphatase-2A catalytic subunit and supports the ERK pathway through dephosphorylation of regulatory proteins. It plays a role in malignant glioma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 14		NP_001258522.1
PPME1	XM_047427116.1	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 12		XP_047283072.1
PPME1	XM_017017913.3	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.287C>T	p.Thr96Met	missense_variant, splice_region_variant	Exon 3 of 14	1		ENSP00000381461.4
PPME1	ENST00000542710.3	n.442C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	3
PPME1	ENST00000544401.2	n.366C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247364 AF XY: 0.00000746

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455476 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 724298

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1106810

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287C>T (p.T96M) alteration is located in exon 3 (coding exon 3) of the PPME1 gene. This alteration results from a C to T substitution at nucleotide position 287, causing the threonine (T) at amino acid position 96 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		4.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.56		Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);
MVP		0.66
MPC		1.3
ClinPred		0.92	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.64
gMVP		0.79
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.11		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: rs79972734; hg19: chr11-73915489;