chr2-240868890-A-AC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000030.3(AGXT):c.33dup(p.Lys12GlnfsTer156) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,610,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.33dup | p.Lys12GlnfsTer156 | frameshift_variant | 1/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.33dup | p.Lys12GlnfsTer156 | frameshift_variant | 1/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000472436.1 | n.53dup | non_coding_transcript_exon_variant | 1/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000126 AC: 19AN: 151008Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.000155 AC: 226AN: 1459284Hom.: 0 Cov.: 31 AF XY: 0.000167 AC XY: 121AN XY: 725858
GnomAD4 genome AF: 0.000132 AC: 20AN: 151122Hom.: 0 Cov.: 33 AF XY: 0.000122 AC XY: 9AN XY: 73852
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Pathogenic:18Other:1
Pathogenic, no assertion criteria provided | clinical testing | Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University | Aug 26, 2024 | Variant_type:truncating/MutationTaster:NONE/CADD:NONE/phyloP:NONE/phastCons:NONE/gnomAD_exome_EastAsian:NONE/ExAC_EastAsian:NONE/dbSNP:NONE - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000140583). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | Mar 10, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The homozgous c.33dupC variant was identified by our study in one individual with Hyperoxaluria. The c.33dupC is a well-established known pathogenic variant (https://www.ncbi.nlm.nih.gov/books/NBK1283/) and loss of function is a known mechanism of disease in the AGXT gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Jan 17, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2022 | - - |
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type 1 (MIM#259900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 19 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It accounts for approximately 30% of disease-causing alleles and is consistently classified as pathogenic by diagnostic laboratories in ClinVar (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is classified as pathogenic in the context of primary hyperoxaluria type 1. Sources cited for classification include the following: PMID 17495019. Classification of NM_000030.2(AGXT):c.33dupC(K12Qfs*156) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 11, 2021 | PVS1, PS3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift AGXT (p.Lys12GlnfsTer156) is one of the most common variant reported in individuals affected with primary hyperoxaluria (Rumsby G. et. al., 2004; Williams EL et. al., 2009). This variant has been reported previously in homozygous state in patients affected with Hyperoxaluria, primary, type 1 (Theodossiadis, P. G. et. al., 2002). The p.Lys12GlnfsTer156 variant is novel (not in any individuals) in 1000 Genomes. This variant causes a frameshift starting with codon Lysine 12, changes this amino acid to Glutamine residue, and creates a premature stop codon at position 156 of the new reading frame, denoted p.Lys12GlnfsTer156. This variant has been reported to the ClinVar database as Pathogenic. Loss-of-function variant in AGXT are known to be Pathogenic (Williams EL et. al., 2009). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Lys12Glnfs*156) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 15327387, 19479957, 25629080, 27135212). This variant is also known as 33_34insC. ClinVar contains an entry for this variant (Variation ID: 140583). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32556641, 31980526, 15110324, 31102713, 29127259, 29456205, 30655312, 30341509, 28619084, 10453743, 20549407, 16931222, 27135212, 28969594) - |
AGXT-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 21, 2023 | The AGXT c.33dupC variant is predicted to result in a frameshift and premature protein termination (p.Lys12Glnfs*156). This variant has been reported to be pathogenic for primary hyperoxaluria (Mayordomo-Colunga et al. 2011. PubMed ID: 20549407). This variant is reported in 0.026% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-241808307-A-AC). Frameshift variants in AGXT are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Primary hyperoxaluria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 24, 2018 | Variant summary: AGXT c.33dupC (p.Lys12GlnfsX156) 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 allele was found at a frequency of 0.00016 in 30572 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (0.00047 vs 0.0024), allowing no conclusion about variant significance. c.33dupC has been reported in the literature in a multiple affected individuals with Primary Hyperoxaluria Type 1 (Rumsby_2004, Mbarek_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Rumsby 2004). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Alanine glyoxylate aminotransferase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Apr 11, 2023 | This sequence change in AGXT is a frameshift variant predicted to cause a premature stop codon, p.(Lys12Glnfs*156), in biologically relevant exon 4/11 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.02% (1/4,750 alleles) in the South Asian population, which is consistent with recessive disease. The variant is one of the most commonly reported pathogenic variants in AGXT. It has been identified in the homozygous state and compound heterozygous with a second pathogenic variant in multiple individuals with clinical/biochemical diagnosis of primary hyperoxaluria (PMID: 15110324, 20301460). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at