rs863225086

Positions:

• chr15-74897663-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;T;.
Eigen	Benign	-0.036
Eigen_PC	Benign	0.041
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.43	T
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	D
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

Other links and lift over

dbSNP: rs863225086; hg19: chr15-75190004;