rs745426479
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_013339.4(ALG6):c.257+2dupT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,449,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
ALG6
NM_013339.4 splice_region, intron
NM_013339.4 splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.67
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 Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
PP5
Variant 1-63402344-G-GT is Pathogenic according to our data. Variant chr1-63402344-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG6 | NM_013339.4 | c.257+2dupT | splice_region_variant, intron_variant | ENST00000263440.6 | NP_037471.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALG6 | ENST00000263440.6 | c.257+2dupT | splice_region_variant, intron_variant | 5 | NM_013339.4 | ENSP00000263440.5 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250878Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135658
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GnomAD4 exome AF: 0.0000159 AC: 23AN: 1449290Hom.: 0 Cov.: 28 AF XY: 0.0000249 AC XY: 18AN XY: 721748
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GnomAD4 genome Cov.: 31
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
ALG6-congenital disorder of glycosylation 1C Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2021 | Variant summary: ALG6 c.257+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 4 (reported as skipping of exon 3 under a legacy naming convention) (Newell_2003). The variant allele was found at a frequency of 1.6e-05 in 250878 control chromosomes. c.257+2dupT has been reported in the literature as IVS3+ 2_3insT in at-least one individual affected with Congenital Disorder Of Glycosylation Type 1C (example, Newell_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change falls in intron 4 of the ALG6 gene. It does not directly change the encoded amino acid sequence of the ALG6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs745426479, gnomAD 0.01%). This variant has been observed in individual(s) with ALG6-related conditions (PMID: 12855228). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3 + 2_3T. ClinVar contains an entry for this variant (Variation ID: 550168). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4, also known as exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 12855228). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at