4-177434387-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000027.4(AGA):βc.800_801insTβ(p.Pro268AlafsTer52) 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 (β β ). Synonymous variant affecting the same amino acid position (i.e. L267L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000027.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGA | NM_000027.4 | c.800_801insT | p.Pro268AlafsTer52 | frameshift_variant | 7/9 | ENST00000264595.7 | |
AGA | NM_001171988.2 | c.770_771insT | p.Pro258AlafsTer52 | frameshift_variant | 7/9 | ||
AGA | NR_033655.2 | n.786_787insT | non_coding_transcript_exon_variant | 6/8 | |||
AGA | XM_047449722.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGA | ENST00000264595.7 | c.800_801insT | p.Pro268AlafsTer52 | frameshift_variant | 7/9 | 1 | NM_000027.4 | P1 | |
AGA | ENST00000502310.5 | c.371_372insT | p.Pro125AlafsTer? | frameshift_variant | 4/5 | 5 | |||
AGA | ENST00000506853.5 | n.758_759insT | non_coding_transcript_exon_variant | 6/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251484Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461494Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727082
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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, no assertion criteria provided | literature only | OMIM | Dec 15, 1991 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 12, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 10, 2023 | - - |
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. - |
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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at