rs202095654

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_006302.3(MOGS):c.858G>C(p.Gln286His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

MOGS
NM_006302.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.260

Variant links:

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]

MOGS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.015684366).

BP6

Variant 2-74462931-C-G is Benign according to our data. Variant chr2-74462931-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000683 (104/152368) while in subpopulation AFR AF= 0.00236 (98/41592). AF 95% confidence interval is 0.00198. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MOGS	NM_006302.3 linkuse as main transcript	c.858G>C	p.Gln286His	missense_variant	4/4	ENST00000448666.7
MOGS	NM_001146158.2 linkuse as main transcript	c.540G>C	p.Gln180His	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MOGS	ENST00000448666.7 linkuse as main transcript	c.858G>C	p.Gln286His	missense_variant	4/4	1	NM_006302.3	P1	Q13724-1

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

249384

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.000201

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152368

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

Bravo

AF:

0.000778

ESP6500AA

AF:

0.00202

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.858G>C (p.Q286H) alteration is located in exon 4 (coding exon 4) of the MOGS gene. This alteration results from a G to C substitution at nucleotide position 858, causing the glutamine (Q) at amino acid position 286 to be replaced by a histidine (H). 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

Jan 08, 2024

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 286 of the MOGS protein (p.Gln286His). This variant is present in population databases (rs202095654, gnomAD 0.2%). 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: 465844). 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 not expected to disrupt MOGS protein function with a negative predictive value of 80%. 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. -

MOGS-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.0086

T;T;.;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.57

M_CAP

Benign

0.0056

MetaRNN

Benign

0.016

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;.;.;.;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

N;N;.;.;N;.

REVEL

Benign

0.013

Sift

Uncertain

0.0080

D;T;.;.;T;.

Polyphen

0.0020

B;B;.;.;.;.

Vest4

0.14, 0.18

MutPred

0.40

Loss of MoRF binding (P = 0.1367);Loss of MoRF binding (P = 0.1367);.;.;.;.;

MVP

0.38

MPC

0.22

ClinPred

0.0074

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.059

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over