rs386833436
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000027.4(AGA):c.800dupT(p.Pro268fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
AGA
NM_000027.4 frameshift
NM_000027.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.85
Genes affected
AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-177434387-C-CA is Pathogenic according to our data. Variant chr4-177434387-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225.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 |
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AGA | NM_000027.4 | c.800dupT | p.Pro268fs | frameshift_variant | 7/9 | ENST00000264595.7 | NP_000018.2 | |
AGA | NM_001171988.2 | c.770dupT | p.Pro258fs | frameshift_variant | 7/9 | NP_001165459.1 | ||
AGA | NR_033655.2 | n.786dupT | non_coding_transcript_exon_variant | 6/8 | ||||
AGA | XM_047449722.1 | c.*94dupT | downstream_gene_variant | XP_047305678.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGA | ENST00000264595.7 | c.800dupT | p.Pro268fs | frameshift_variant | 7/9 | 1 | NM_000027.4 | ENSP00000264595.2 | ||
AGA | ENST00000502310.5 | c.371dupT | p.Pro125fs | frameshift_variant | 4/5 | 5 | ENSP00000423798.1 | |||
AGA | ENST00000506853.5 | n.758dupT | non_coding_transcript_exon_variant | 6/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461494Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727082
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2018 | Variant summary: AGA c.800dupT (p.Pro268AlafsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was observed with an allele freqyency of 2.8e-05 in 246258 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AGA causing Aspartylglucosaminuria (2.8e-05 vs 0.0049), allowing no conclusion about variant significance. The variant, c.800dupT, has been reported in the literature in a homozygous individual affected with Aspartylglucosaminuria, who presented with less than 10% normal AGA activity (Ikonen_1991). These data indicate that the variant may be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 12, 2016 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Pro268Alafs*52) in the AGA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the AGA protein. This variant is present in population databases (rs386833436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with aspartylglucosaminuria (PMID: 1722323). ClinVar contains an entry for this variant (Variation ID: 225). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects AGA function (PMID: 1722323, 11309371). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 11, 2021 | The c.800dupT (p.P268Afs*52) alteration, located in exon 7 (coding exon 7) of the AGA gene, consists of a duplication of T at position 800, causing a translational frameshift with a predicted alternate stop codon after 52 amino acids. This alteration occurs at the 3' terminus of the AGA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 79 amino acids of the protein. However, premature stop codons are typically deleterious in nature. Based on data from the Genome Aggregation Database (gnomAD) database, the AGA c.800dupT alteration was observed in 0.003% (7/251484) of total alleles studied, with a frequency of 0.02% (6/34592) in the Latino subpopulation. This alteration has been detected in a homozygous state in an individual with aspartylglucosaminidase, which was diagnosed via clinical features, detection of urinary glycoasparagines, and decreased AGA activity (Ikonen, 1991). This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2024 | Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 11309371); Frameshift variant predicted to result in abnormal protein length as the last 79 amino acids are replaced with 51 different amino acids, and other similar variants have been reported in HGMD; Also known as c.800_801insT; This variant is associated with the following publications: (PMID: 1722323, 11309371) - |
Computational scores
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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