NM_006302.3:c.2017G>A

Variant names:

• chr2-74461772-C-T
• rs114933392
• NM_006302.3:c.2017G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006302.3(MOGS):​c.2017G>A​(p.Val673Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,614,216 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V673A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (17 hom., cov: 33)
  • Exomes 𝑓: 0.011 (137 hom.)
• Consequence: MOGS NM_006302.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.23
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• MOGS-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005691737).
• BP6: Variant 2-74461772-C-T is Benign according to our data. Variant chr2-74461772-C-T is described in ClinVar as Benign. ClinVar VariationId is 218681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00983 (1498/152338) while in subpopulation NFE AF = 0.0125 (852/68036). AF 95% confidence interval is 0.0118. There are 17 homozygotes in GnomAd4. There are 771 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006302.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOGS	NM_006302.3	MANE Select	c.2017G>A	p.Val673Ile	missense	Exon 4 of 4	NP_006293.2
	MOGS	NM_001146158.2		c.1699G>A	p.Val567Ile	missense	Exon 5 of 5	NP_001139630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOGS	ENST00000448666.7	TSL:1 MANE Select	c.2017G>A	p.Val673Ile	missense	Exon 4 of 4	ENSP00000410992.3
	MOGS	ENST00000452063.7	TSL:1	c.1699G>A	p.Val567Ile	missense	Exon 5 of 5	ENSP00000388201.2
	MOGS	ENST00000649854.1		c.1648G>A	p.Val550Ile	missense	Exon 3 of 3	ENSP00000496797.1

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152220 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0112 AC: 2800 AN: 249470 AF XY: 0.0115

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.0249

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0109 AC: 15944 AN: 1461878 Hom.: 137 Cov.: 31 AF XY: 0.0110 AC XY: 8013 AN XY: 727238

African (AFR) AF: 0.00197 AC: 66 AN: 33478

American (AMR) AF: 0.00324 AC: 145 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 610 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00616 AC: 531 AN: 86258

European-Finnish (FIN) AF: 0.0351 AC: 1872 AN: 53408

Middle Eastern (MID) AF: 0.0225 AC: 130 AN: 5768

European-Non Finnish (NFE) AF: 0.0107 AC: 11929 AN: 1112010

Other (OTH) AF: 0.0109 AC: 660 AN: 60396

GnomAD4 genome AF: 0.00983 AC: 1498 AN: 152338 Hom.: 17 Cov.: 33 AF XY: 0.0104 AC XY: 771 AN XY: 74492

African (AFR) AF: 0.00207 AC: 86 AN: 41578

American (AMR) AF: 0.00470 AC: 72 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.0327 AC: 347 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 852 AN: 68036

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0110 Hom.: 41

Bravo AF: 0.00756

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00231 AC: 9

ESP6500EA AF: 0.0114 AC: 94

ExAC AF: 0.0107 AC: 1291

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0128

EpiControl AF: 0.0135

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	MOGS-congenital disorder of glycosylation (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.043
Sift	Benign	0.41	T
Sift4G	Benign	0.42	T
Polyphen		0.071	B
Vest4		0.032
MPC		0.20
ClinPred		0.0024	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.30
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114933392; hg19: chr2-74688899; COSMIC: COSV51972342; COSMIC: COSV51972342;