chr1-63415875-TTTG-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5
The NM_013339.4(ALG6):c.908_910delGTT(p.Cys303del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,600,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
ALG6
NM_013339.4 disruptive_inframe_deletion
NM_013339.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.22
Genes affected
ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity ALG6_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_013339.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_013339.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 1-63415875-TTTG-T is Pathogenic according to our data. Variant chr1-63415875-TTTG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372732.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000131 AC: 19AN: 1448018Hom.: 0 AF XY: 0.0000166 AC XY: 12AN XY: 721146
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GnomAD4 genome 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 16, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2022 | Variant summary: ALG6 c.908_910delGTT (p.Cys303del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 249388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.908_910delGTT has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual affected with alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) (example, Morava_2016) and also listed without a second allele or zygosity specified in a mutational update report (example, Haeuptle_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2016 | The c.908_910delGTT variant in the ALG6 gene has been previously reported in an least one individual with CDG who had a second variant, c.257+5G>A, although the phase for these two variants is unknown (Morava et al., 2016). The c.908_910delGTT variant causes an in-frame deletion of one amino acid, Cysteine 303, denoted p.C303del. This amino acid deletion occurs at a position that is not conserved across species. However, the c.908_910delGTT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.908_910delGTT as a likely pathogenic variant. - |
Computational scores
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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