rs863225086
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4
The NM_002435.3(MPI):c.1205A>G(p.Glu402Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
MPI
NM_002435.3 missense
NM_002435.3 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 6.99
Genes affected
MPI (HGNC:7216): (mannose phosphate isomerase) Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate and plays a critical role in maintaining the supply of D-mannose derivatives, which are required for most glycosylation reactions. Mutations in the MPI gene were found in patients with carbohydrate-deficient glycoprotein syndrome, type Ib. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-74897663-A-G is Pathogenic according to our data. Variant chr15-74897663-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 218094.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.37930197). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPI | NM_002435.3 | c.1205A>G | p.Glu402Gly | missense_variant | 8/8 | ENST00000352410.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPI | ENST00000352410.9 | c.1205A>G | p.Glu402Gly | missense_variant | 8/8 | 1 | NM_002435.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 exome
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2
AN:
1461888
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33
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0
AN XY:
727244
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MPI-congenital disorder of glycosylation Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute | - | This variant was identified in a male who presented clinically normal until the age of 2 when he became ill with persistent vomiting and venous sinus thrombosis which resulted in a massive stroke. Subsequently he developed a seizure disorder and delayed development. Full metabolic work up was normal except for the presence of a Type I CDG profile. Given his history of normal development prior to the stroke, MPI-CDG was suggested. Enzyme assay concluded he had MPI-CDG. The enzyme assay was performed as previously reported from the Freeze lab, PMID: 9525984. “Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy.” Genetic analysis revealed two single nucleotide variants inherited in a compound heterozygous fashion, NM_002435.2:c.1205A>G and NM_002435.2:c.1253G>A. The c.1205A>G variant has not been previously reported in ExAc, dbSNP, or ESP. The predicted protein change for NM_002435.2:c.1205A>G is a Glutamate to Glycine; this residue is moderately conserved (Glu in humans through zebrafish). MutationTaster predicts this mutation to be deleterious. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
B;.;.;B
Vest4
MutPred
Gain of ubiquitination at K407 (P = 0.1084);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at