rs576166441
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_006302.3(MOGS):āc.436T>Gā(p.Tyr146Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,613,950 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 (ā ā ).
Frequency
Genomes: š 0.000026 ( 0 hom., cov: 33)
Exomes š: 0.000051 ( 0 hom. )
Consequence
MOGS
NM_006302.3 missense
NM_006302.3 missense
Scores
8
4
3
Clinical Significance
Conservation
PhyloP100: 6.12
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 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, 0.967
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MOGS | NM_006302.3 | c.436T>G | p.Tyr146Asp | missense_variant | 2/4 | ENST00000448666.7 | |
MOGS | NM_001146158.2 | c.118T>G | p.Tyr40Asp | missense_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MOGS | ENST00000448666.7 | c.436T>G | p.Tyr146Asp | missense_variant | 2/4 | 1 | NM_006302.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249382Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135370
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727178
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2023 | The c.436T>G (p.Y146D) alteration is located in exon 2 (coding exon 2) of the MOGS gene. This alteration results from a T to G substitution at nucleotide position 436, causing the tyrosine (Y) at amino acid position 146 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
MOGS-congenital disorder of glycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 146 of the MOGS protein (p.Tyr146Asp). This variant is present in population databases (rs576166441, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MOGS-related conditions. ClinVar contains an entry for this variant (Variation ID: 465842). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MOGS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
REVEL
Pathogenic
Polyphen
D;D;.;.;.;.;.
Vest4
0.82, 0.88, 0.83
MutPred
Gain of disorder (P = 0.0057);Gain of disorder (P = 0.0057);Gain of disorder (P = 0.0057);.;Gain of disorder (P = 0.0057);.;.;
MVP
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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