11-74246081-G-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.840G>C(p.Lys280Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 1,580,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PPME1 NM_016147.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

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]

P4HA3 (HGNC:30135): (prolyl 4-hydroxylase subunit alpha 3) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

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=0.19687077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPME1	NM_016147.3	c.840G>C	p.Lys280Asn	missense_variant	10/14	ENST00000328257.13
PPME1	NM_001271593.2	c.882G>C	p.Lys294Asn	missense_variant	10/14
PPME1	XM_047427116.1	c.840G>C	p.Lys280Asn	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPME1	ENST00000328257.13	c.840G>C	p.Lys280Asn	missense_variant	10/14	1	NM_016147.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000100 AC: 2 AN: 199534 Hom.: 0 AF XY: 0.00000942 AC XY: 1 AN XY: 106114

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000233

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000252 AC: 36 AN: 1428458 Hom.: 0 Cov.: 30 AF XY: 0.0000170 AC XY: 12 AN XY: 706906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000249

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: 0.0000320

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

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

Dec 27, 2023

The c.840G>C (p.K280N) alteration is located in exon 10 (coding exon 10) of the PPME1 gene. This alteration results from a G to C substitution at nucleotide position 840, causing the lysine (K) at amino acid position 280 to be replaced by an asparagine (N). 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	0.36
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.083	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.16
Sift	Benign	0.29	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.27	B;.
Vest4		0.29
MutPred		0.56		Loss of methylation at K280 (P = 0.0012);.;
MVP		0.30
MPC		0.64
ClinPred		0.24	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.28
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs929778503; hg19: chr11-73957126;