dbSNP rs863225086: MPI:p.Glu402Gly (chr15-74897663-A-G) – ACMG Classification: Uncertain_significance (3 pts)

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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.99

Variant links:

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]

MPI links:

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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 rank	MANE	Protein	UniProt
MPI	NM_002435.3 link	c.1205A>G	p.Glu402Gly	missense_variant	Exon 8 of 8	ENST00000352410.9	NP_002426.1	P34949-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9 link	c.1205A>G	p.Glu402Gly	missense_variant	Exon 8 of 8	1	NM_002435.3	ENSP00000318318.6		P34949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MPI-congenital disorder of glycosylation

Pathogenic:1

Sanford Children's Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.;T;.

Eigen

Benign

-0.036

Eigen_PC

Benign

0.041

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.0

M;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.029

B;.;.;B

Vest4

0.47

MutPred

0.51

Gain of ubiquitination at K407 (P = 0.1084);.;.;.;

MVP

0.91

MPC

0.22

ClinPred

0.99

GERP RS

4.4

Varity_R

0.32

gMVP

0.81

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

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