rs587777323
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006302.3(MOGS):c.370C>T(p.Gln124Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,910 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
MOGS
NM_006302.3 stop_gained
NM_006302.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 8.47
Genes affected
MOGS (HGNC:24862): (mannosyl-oligosaccharide glucosidase) This gene encodes the first enzyme in the N-linked oligosaccharide processing pathway. The enzyme cleaves the distal alpha-1,2-linked glucose residue from the Glc(3)-Man(9)-GlcNAc(2) oligosaccharide precursor. This protein is located in the lumen of the endoplasmic reticulum. Defects in this gene are a cause of type IIb congenital disorder of glycosylation (CDGIIb). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-74464705-G-A is Pathogenic according to our data. Variant chr2-74464705-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 127098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74464705-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MOGS | NM_006302.3 | c.370C>T | p.Gln124Ter | stop_gained | 2/4 | ENST00000448666.7 | |
MOGS | NM_001146158.2 | c.52C>T | p.Gln18Ter | stop_gained | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MOGS | ENST00000448666.7 | c.370C>T | p.Gln124Ter | stop_gained | 2/4 | 1 | NM_006302.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152248Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247112Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134348
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460662Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 726462
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
MOGS-congenital disorder of glycosylation Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | This sequence change creates a premature translational stop signal (p.Gln124*) in the MOGS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MOGS are known to be pathogenic (PMID: 24716661, 26805780). This variant is present in population databases (rs587777323, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with MOGS-congenital disorder of glycosylation (PMID: 26805780). ClinVar contains an entry for this variant (Variation ID: 127098). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Jan 12, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2020 | Nonsense variant predicted to result in protein truncation [or nonsense mediated decay] in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26805780, 24716661, 29431110) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;D
Vest4
0.31, 0.30
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at