15-74890086-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002435.3(MPI):c.13C>T(p.Arg5Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,607,920 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
MPI
NM_002435.3 stop_gained
NM_002435.3 stop_gained
Scores
1
1
5
Clinical Significance
Conservation
PhyloP100: -0.256
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 15-74890086-C-T is Pathogenic according to our data. Variant chr15-74890086-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPI | NM_002435.3 | c.13C>T | p.Arg5Ter | stop_gained | 1/8 | ENST00000352410.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPI | ENST00000352410.9 | c.13C>T | p.Arg5Ter | stop_gained | 1/8 | 1 | NM_002435.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000687 AC: 10AN: 1455740Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5AN XY: 724540
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MPI-congenital disorder of glycosylation Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 03, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 554184). This variant has not been reported in the literature in individuals affected with MPI-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg5*) in the MPI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPI are known to be pathogenic (PMID: 19862844). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A;N;N;N;N
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at