rs79972734

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-74204444-C-G
• chr11-74204444-C-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>G​(p.Thr96Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. T96M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPME1 NM_016147.3 missense, splice_region
• Scores: Splicing: ADA: 0.9853
• Clinical Significance: Not reported in ClinVar
• 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>G	p.Thr96Arg	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.287C>G	p.Thr96Arg	missense_variant, splice_region_variant	Exon 3 of 14		NP_001258522.1
PPME1	XM_047427116.1	c.287C>G	p.Thr96Arg	missense_variant, splice_region_variant	Exon 3 of 12		XP_047283072.1
PPME1	XM_017017913.3	c.287C>G	p.Thr96Arg	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>G	p.Thr96Arg	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.287C>G	p.Thr96Arg	missense_variant, splice_region_variant	Exon 3 of 14	1		ENSP00000381461.4
PPME1	ENST00000542710.3	n.442C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4	3
PPME1	ENST00000544401.2	n.366C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		4.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.83		Gain of MoRF binding (P = 0.0166);Gain of MoRF binding (P = 0.0166);
MVP		0.78
MPC		1.2
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.95
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.19		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;