rs748090636
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002435.3(MPI):c.748G>A(p.Gly250Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,038 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: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
MPI
NM_002435.3 missense
NM_002435.3 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 9.72
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]
Genome browser will be placed here
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, 0.987
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPI | NM_002435.3 | c.748G>A | p.Gly250Ser | missense_variant | 6/8 | ENST00000352410.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPI | ENST00000352410.9 | c.748G>A | p.Gly250Ser | missense_variant | 6/8 | 1 | NM_002435.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152150Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
9
AN:
152150
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251482Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD3 exomes
AF:
AC:
4
AN:
251482
Hom.:
AF XY:
AC XY:
2
AN XY:
135912
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 exome
AF:
AC:
11
AN:
1461888
Hom.:
Cov.:
31
AF XY:
AC XY:
4
AN XY:
727246
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
GnomAD4 genome
?
AF:
AC:
9
AN:
152150
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74328
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
?
AF:
AC:
2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MPI-congenital disorder of glycosylation Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MPI-related disorder (PMID: 10980531). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2023 | Variant summary: MPI c.748G>A (p.Gly250Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251482 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.748G>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation (e.g. Schollen_2000, Lipinski_2021, Bogdanska_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33407696, 33643843, 10980531). Three ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 10, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;.;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;D
Sift
Pathogenic
D;D;D;D;D;D;D;T;D;T
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;D;.;.;D;.;.
Vest4
0.96, 0.98, 0.91, 0.85, 0.99, 0.98, 0.95, 0.92
MutPred
0.95
.;Loss of catalytic residue at P246 (P = 0.069);Loss of catalytic residue at P246 (P = 0.069);Loss of catalytic residue at P246 (P = 0.069);.;.;.;.;.;.;
MVP
MPC
0.74
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