Variant 18-11889404-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000588072.6(MPPE1):c.477C>G(p.Asp159Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MPPE1
ENST00000588072.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.56

Variant links:

Genes affected

MPPE1 (HGNC:15988): (metallophosphoesterase 1) Predicted to enable GPI anchor binding activity; GPI-mannose ethanolamine phosphate phosphodiesterase activity; and manganese ion binding activity. Involved in GPI anchor biosynthetic process. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MPPE1 links:

MPPE1 (HGNC:):

MPPE1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPPE1	NM_023075.6 linkuse as main transcript	c.477C>G	p.Asp159Glu	missense_variant	5/11	ENST00000588072.6	NP_075563.3	Q53F39-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPPE1	ENST00000588072.6 linkuse as main transcript	c.477C>G	p.Asp159Glu	missense_variant	5/11	1	NM_023075.6	ENSP00000465894.1		Q53F39-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249962

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458962

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725966

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.477C>G (p.D159E) alteration is located in exon 5 (coding exon 3) of the MPPE1 gene. This alteration results from a C to G substitution at nucleotide position 477, causing the aspartic acid (D) at amino acid position 159 to be replaced by a glutamic acid (E). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;T;T;.;D;.;D

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;.;D;D;T;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.6

H;H;H;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.9

.;D;D;D;.;.;.;.;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

.;D;D;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.;D;.

Polyphen

1.0

D;D;D;.;.;.;.;.;.

Vest4

0.97

MutPred

0.89

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.85

MPC

0.54

ClinPred

1.0

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over