NM_019109.5:c.1250_1251insTG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_019109.5(ALG1):c.1250_1251insTG(p.Ala418GlufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_019109.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALG1 | NM_019109.5 | c.1250_1251insTG | p.Ala418GlufsTer18 | frameshift_variant | Exon 12 of 13 | ENST00000262374.10 | NP_061982.3 | |
ALG1 | NM_001330504.2 | c.917_918insTG | p.Ala307GlufsTer18 | frameshift_variant | Exon 12 of 13 | NP_001317433.1 | ||
ALG1 | XM_017023457.3 | c.1211_1212insTG | p.Ala405GlufsTer18 | frameshift_variant | Exon 11 of 12 | XP_016878946.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000128 AC: 3AN: 235286Hom.: 0 AF XY: 0.0000233 AC XY: 3AN XY: 128800
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000553 AC: 8AN: 1445530Hom.: 0 Cov.: 34 AF XY: 0.00000695 AC XY: 5AN XY: 719520
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
ALG1-congenital disorder of glycosylation Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Ala418Glufs*18) in the ALG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the ALG1 protein. This variant is present in population databases (rs746019074, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital disorders of glycosylation (PMID: 26453362, 26931382). ClinVar contains an entry for this variant (Variation ID: 424339). This variant disrupts the p.Arg438 amino acid residue in ALG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20679665, 26931382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Congenital disorder of glycosylation Pathogenic:1
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not provided Pathogenic:1
Frameshift variant predicted to result in abnormal protein length as the last 47 amino acids are replaced with 17 different amino acids, and other similar variants have been reported in HGMD; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26931382, 20679665, 26453362) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at