rs121907931
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_024105.4(ALG12):c.200C>T(p.Thr67Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,624 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
ALG12
NM_024105.4 missense
NM_024105.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 7.64
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 22-49913480-G-A is Pathogenic according to our data. Variant chr22-49913480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3434.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr22-49913480-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG12 | NM_024105.4 | c.200C>T | p.Thr67Met | missense_variant | 3/10 | ENST00000330817.11 | NP_077010.1 | |
ALG12 | XM_017028936.2 | c.200C>T | p.Thr67Met | missense_variant | 3/10 | XP_016884425.1 | ||
ALG12 | XM_017028937.2 | c.200C>T | p.Thr67Met | missense_variant | 3/11 | XP_016884426.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALG12 | ENST00000330817.11 | c.200C>T | p.Thr67Met | missense_variant | 3/10 | 1 | NM_024105.4 | ENSP00000333813.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
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34
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251280Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135872
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461624Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727116
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GnomAD4 genome Cov.: 34
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34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
ALG12-congenital disorder of glycosylation Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2022 | 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. Experimental studies have shown that this missense change affects ALG12 function (PMID: 12217961). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 3434). This missense change has been observed in individual(s) with ALG12-related conditions (PMID: 12217961). This variant is present in population databases (rs121907931, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 67 of the ALG12 protein (p.Thr67Met). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2024 | Variant summary: ALG12 c.200C>T (p.Thr67Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251280 control chromosomes (gnomAD). c.200C>T has been reported in the literature in the compound heterozygous state in at least two in individuals affected with ALG12-Congenital Disorder Of Glycosylation (Grubenmann_2002, Vleugels_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Grubenmann_2002). The results showed the variant was unable to fully restore growth in a yeast complementation assay. The following publications have been ascertained in the context of this evaluation (PMID: 12217961, 21315133). ClinVar contains an entry for this variant (Variation ID: 3434). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at T67 (P = 0.042);
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