rs13405869

Positions:

• chr2-74461757-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000448666.7(MOGS):​c.2032C>T​(p.Arg678Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,614,170 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R678L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (148 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (127 hom.)
• Consequence: MOGS ENST00000448666.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.284

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004419416).
• BP6: Variant 2-74461757-G-A is Benign according to our data. Variant chr2-74461757-G-A is described in ClinVar as [Benign]. Clinvar id is 337105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MOGS	NM_006302.3	c.2032C>T	p.Arg678Trp	missense_variant	4/4	ENST00000448666.7	NP_006293.2
MOGS	NM_001146158.2	c.1714C>T	p.Arg572Trp	missense_variant	5/5		NP_001139630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MOGS	ENST00000448666.7	c.2032C>T	p.Arg678Trp	missense_variant	4/4	1	NM_006302.3	ENSP00000410992	P1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3516 AN: 152176 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.0801

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00587 AC: 1464 AN: 249522 Hom.: 66 AF XY: 0.00425 AC XY: 576 AN XY: 135392

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00241 AC: 3523 AN: 1461876 Hom.: 127 Cov.: 31 AF XY: 0.00204 AC XY: 1483 AN XY: 727240

Gnomad4 AFR exome AF: 0.0832

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.0232 AC: 3527 AN: 152294 Hom.: 148 Cov.: 33 AF XY: 0.0214 AC XY: 1594 AN XY: 74474

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00507 Hom.: 65

Bravo AF: 0.0263

ESP6500AA AF: 0.0779 AC: 309

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00708 AC: 856

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MOGS-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T;T;.;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	.;D;.;D;D
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.;.;.
MutationTaster	Benign	0.0011	P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	.;D;.;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.026	.;D;.;.;D
Sift4G	Uncertain	0.014	.;D;.;.;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.38, 0.38
MVP		0.47
MPC		0.76
ClinPred		0.043	T
GERP RS		-0.26
Varity_R		0.12
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs13405869; hg19: chr2-74688884;