NM_000030.3:c.116_117dupCA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000030.3(AGXT):c.116_117dupCA(p.Ala40GlnfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,922 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
Consequence
NM_000030.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247578Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134588
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460740Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 726670
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:3
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not provided Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 204175). This variant is also known as 117_118insCA. This premature translational stop signal has been observed in individual(s) with clinical features of primary hyperoxaluria (PMID: 15963748). This variant is present in population databases (rs762245382, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Ala40Glnfs*7) in the AGXT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). -
PS4_moderate, PVS1 -
Primary hyperoxaluria Pathogenic:1
Variant summary: AGXT c.116_117dupCA (p.Ala40GlnfsX7) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-05 in 247578 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.0024), allowing no conclusion about variant significance.c.116_117dupCA has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (Coulter-Mackie_2005, Williams_2007, Williams_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at