rs762811727
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001425242.1(ALG8):c.-16C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,606,700 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 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
ALG8
NM_001425242.1 5_prime_UTR_premature_start_codon_gain
NM_001425242.1 5_prime_UTR_premature_start_codon_gain
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.13
Genes affected
ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.499
PP5
Variant 11-78119193-G-A is Pathogenic according to our data. Variant chr11-78119193-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG8 | NM_024079.5 | c.535C>T | p.Arg179* | stop_gained | Exon 5 of 13 | ENST00000299626.10 | NP_076984.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151966Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250972Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135678
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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
Polycystic liver disease 3 with or without kidney cysts Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R179* in ALG8 (NM_024079.5) has been previously reported in heterozygous state in patients with polycystic liver disease (Besse W et al,2017). It has been submitted to ClinVar as Pathogenic based on the same. The p.R179* variant is observed in 1/16,224 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 21, 2018 | - - |
ALG8-related disorder Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 22, 2023 | The ALG8 c.535C>T variant is predicted to result in premature protein termination (p.Arg179*). This variant was firstly reported in the heterozygous state in a polycystic liver disease (PLD) patient who also has kidney cysts (Besse et al. 2017. PubMed ID: 28375157). In a later study of assessing the relationship between truncating ALG8 variants and polycystic kidney disease (PKD), individuals who are heterozygous for ALG8 pathogenic or likely pathogenic variants, including this variant, were shown to have increased risk of a mild (atypical) cystic kidney disease phenotype on imaging (Apple et al. 2023. PubMed ID: 36574950). Of note, the majority of loss-of-function variants in ALG8 have been reported in association with autosomal recessive congenital disorder of glycosylation (Human Gene Mutation Database). This variant is reported in 7 of 282,326 alleles in the gnomAD database. Nonsense variants in ALG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic for autosomal recessive ALG8-related disorders. For autosomal dominant polycystic kidney-spectrum phenotype, however, it is currently uncertain since there is limited evidence to support the gene-disease relationship (ALG8 at https://www.clinicalgenome.org/). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 22, 2023 | PVS1, PS3_Moderate - |
ALG8 congenital disorder of glycosylation;C4693472:Polycystic liver disease 3 with or without kidney cysts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 18, 2023 | PP2, PVS1 - |
ALG8 congenital disorder of glycosylation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Arg179*) in the ALG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG8 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs762811727, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with kidney and/or liver cysts (PMID: 28375157, 36574950). ClinVar contains an entry for this variant (Variation ID: 492977). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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