rs1057520122
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_019109.5(ALG1):c.1150G>A(p.Gly384Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,611,750 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). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_019109.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG1 | NM_019109.5 | c.1150G>A | p.Gly384Arg | missense_variant | 11/13 | ENST00000262374.10 | |
ALG1 | NM_001330504.2 | c.817G>A | p.Gly273Arg | missense_variant | 11/13 | ||
ALG1 | XM_017023457.3 | c.1111G>A | p.Gly371Arg | missense_variant | 10/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG1 | ENST00000262374.10 | c.1150G>A | p.Gly384Arg | missense_variant | 11/13 | 1 | NM_019109.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250422Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135564
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1459536Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 726080
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
ALG1-congenital disorder of glycosylation Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2023 | Variant summary: ALG1 c.1150G>A (p.Gly384Arg) results in a non-conservative amino acid change located in the Glycosyl transferase, family 1 domain (IPR001296) of 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 250422 control chromosomes (gnomAD). The variant, c.1150G>A, has been reported in the literature in at least two compound heterozygous individuals affected with Congenital Disorder of Glycosylation Type 1K (Ng_2016, AbuBakar_2022), and in one of these patients glycomics profiling revealed specific glycomarkers for the disease (AbuBakar_2022). These data indicate that the variant may be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein was not able to fully rescue growth in a yeast complementation assay, and was also unable to fully correct hypoglycosylation defects in the alg1-deficient yeast strain (Ng_2016). Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 384 of the ALG1 protein (p.Gly384Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ALG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 690331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALG1 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Congenital disorder of glycosylation Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | May 25, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at