rs121907932
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_024105.4(ALG12):c.437G>A(p.Arg146Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,640 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
ALG12
NM_024105.4 missense
NM_024105.4 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 7.77
Genes affected
ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant 22-49910466-C-T is Pathogenic according to our data. Variant chr22-49910466-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-49910466-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG12 | NM_024105.4 | c.437G>A | p.Arg146Gln | missense_variant | 4/10 | ENST00000330817.11 | NP_077010.1 | |
ALG12 | XM_017028936.2 | c.437G>A | p.Arg146Gln | missense_variant | 4/10 | XP_016884425.1 | ||
ALG12 | XM_017028937.2 | c.437G>A | p.Arg146Gln | missense_variant | 4/11 | XP_016884426.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALG12 | ENST00000330817.11 | c.437G>A | p.Arg146Gln | missense_variant | 4/10 | 1 | NM_024105.4 | ENSP00000333813 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152214Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000116 AC: 29AN: 250992Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135774
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GnomAD4 exome AF: 0.000121 AC: 177AN: 1461426Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80AN XY: 727008
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GnomAD4 genome AF: 0.000145 AC: 22AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74366
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
ALG12-congenital disorder of glycosylation Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the ALG12 protein (p.Arg146Gln). This variant is present in population databases (rs121907932, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of congenital disorders of glycosylation (PMID: 12217961, 17506107, 30266093, 33461977). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3435). 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 ALG12 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ALG12 function (PMID: 12217961). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 15, 2007 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2022 | Variant summary: ALG12 c.437G>A (p.Arg146Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250992 control chromosomes (gnomAD). c.437G>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation (Grubenmann_2002, Kranz_2007, Normand_2018, Scott_2022). These data indicate that the variant is likely to be associated with disease. A functional yeast complementation assay showed that the variant had very weak rescue ability in an alg12 deficient yeast strain grown with hygromycin B, indicating loss of function (Grubenmann_2002). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Nov 11, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and has been found once in our laboratory in trans with a deleterious frameshift mutation in a fetus with cystic hygroma, VSD, diaphragmatic hernia, brain malformations, and micrognathia; a previous fetus was similarly affected (not tested). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 13, 2017 | - - |
ALG12-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 03, 2023 | The ALG12 c.437G>A variant is predicted to result in the amino acid substitution p.Arg146Gln. This variant has been reported to be causative for autosomal recessive congenital disorder of glycosylation type 1g (CDG1G; OMIM: #607143; Grubenmann et al. 2002. PubMed ID: 12217961; Kranz et al. 2007. PubMed ID: 17506107; Normand et al. 2018. PubMed ID: 30266093). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-50304114-C-T). Given the evidence, we interpret c.437G>A (p.Arg146Gln) as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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