rs745426479
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_013339.4(ALG6):c.257+2dup variant causes a splice donor 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_donor
NM_013339.4 splice_donor
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 13 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05839895 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 21, new splice context is: aatGTaact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
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+2dup | splice_donor_variant | ENST00000263440.6 | NP_037471.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALG6 | ENST00000263440.6 | c.257+2dup | splice_donor_variant | 5 | NM_013339.4 | ENSP00000263440 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
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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 | 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 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at