ENST00000452063.7:c.-8A>G

Variant names:

• chr2-74464937-T-C
• rs1553380245
• ENST00000452063.7:c.-8A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000452063.7(MOGS):​c.-8A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000069 in 1,449,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MOGS ENST00000452063.7 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000452063.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOGS	NM_006302.3	MANE Select	c.311A>G	p.Tyr104Cys	missense	Exon 1 of 4	NP_006293.2
	MOGS	NM_001146158.2		c.-8A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001139630.1
	MOGS	NM_001146158.2		c.-8A>G		5_prime_UTR	Exon 2 of 5	NP_001139630.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MOGS	ENST00000452063.7	TSL:1	c.-8A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000388201.2
	MOGS	ENST00000448666.7	TSL:1 MANE Select	c.311A>G	p.Tyr104Cys	missense	Exon 1 of 4	ENSP00000410992.3
	MOGS	ENST00000452063.7	TSL:1	c.-8A>G		5_prime_UTR	Exon 2 of 5	ENSP00000388201.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449770 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719662

African (AFR) AF: 0.0000300 AC: 1 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 43182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39192

South Asian (SAS) AF: 0.00 AC: 0 AN: 84468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105874

Other (OTH) AF: 0.00 AC: 0 AN: 59822

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.89		Loss of phosphorylation at Y104 (P = 0.0149)
MVP		0.85
MPC		0.97
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.016	Neutral
Varity_R		0.98
gMVP		0.98
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1553380245; hg19: chr2-74692064;