11-74239239-A-C

Position:

• chr11-74239239-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016147.3(PPME1):​c.817A>C​(p.Lys273Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPME1 NM_016147.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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]

PPME1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17915279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPME1	NM_016147.3	c.817A>C	p.Lys273Gln	missense_variant	9/14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.817A>C	p.Lys273Gln	missense_variant	9/14		NP_001258522.1
PPME1	XM_047427116.1	c.817A>C	p.Lys273Gln	missense_variant	9/12		XP_047283072.1
PPME1	XM_017017913.3	c.817A>C	p.Lys273Gln	missense_variant	9/10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.817A>C	p.Lys273Gln	missense_variant	9/14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.817A>C	p.Lys273Gln	missense_variant	9/14	1		ENSP00000381461.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2023

The c.817A>C (p.K273Q) alteration is located in exon 9 (coding exon 9) of the PPME1 gene. This alteration results from a A to C substitution at nucleotide position 817, causing the lysine (K) at amino acid position 273 to be replaced by a glutamine (Q). 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	Benign	0.18
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.14
Sift	Benign	0.44	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.019	B;.
Vest4		0.37
MutPred		0.42		Loss of methylation at K273 (P = 0.0045);Loss of methylation at K273 (P = 0.0045);
MVP		0.45
MPC		0.47
ClinPred		0.73	D
GERP RS		5.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.8
Varity_R		0.22
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-73950284;