rs140992177
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS1
The NM_000030.3(AGXT):c.836T>C(p.Ile279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0029 in 1,614,098 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I279M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000030.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGXT | NM_000030.3 | c.836T>C | p.Ile279Thr | missense_variant | 8/11 | ENST00000307503.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGXT | ENST00000307503.4 | c.836T>C | p.Ile279Thr | missense_variant | 8/11 | 1 | NM_000030.3 | P1 | |
AGXT | ENST00000476698.1 | n.488T>C | non_coding_transcript_exon_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00177 AC: 269AN: 152160Hom.: 1 Cov.: 34
GnomAD3 exomes AF: 0.00182 AC: 457AN: 251244Hom.: 0 AF XY: 0.00191 AC XY: 260AN XY: 135856
GnomAD4 exome AF: 0.00302 AC: 4408AN: 1461820Hom.: 10 Cov.: 35 AF XY: 0.00294 AC XY: 2138AN XY: 727208
GnomAD4 genome ? AF: 0.00177 AC: 269AN: 152278Hom.: 1 Cov.: 34 AF XY: 0.00153 AC XY: 114AN XY: 74458
ClinVar
Submissions by phenotype
Primary hyperoxaluria, type I Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 25, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Biochemistry Laboratory, Health Services Laboratory | Dec 23, 2023 | This variant has been confirmed to be pathogenic in vivo when expressed on the background of the minor allele (AGXT c.32C>T)(PMID:19479957) but, when expressed on the major allele (AGXT c.32C=), it has normal activity in vitro (PID:15963748). Interpretation therefore requires knowledge of the haplotype. ACMG for expression on minor allele:PS3 PM2 PM3 PP3 PP4 BP6 (Pathogenic) ACMG for expression on major allele:PM2 PP3 BS3 BP2 BP6 (likely benign) - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 25, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 08, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 11, 2022 | Variant summary: AGXT c.836T>C (p.Ile279Thr) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 251244 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.836T>C has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 without strong evidence of causality (e.g. Coulter-Mackie_2005, Monico_2007, Hoyer-Kuhn_2014, Mandrile_2014, Hopp_2015). Importantly, co-occurrences of the variant in cis with known pathogenic variants in at least 5 compound heterozygous individuals have been reported (Coulter-Mackie_2005, Monico_2007), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant has essentially normal enzymatic activity (Coulter-Mackie_2005). Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2015 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The AGXT p.Ile279Thr variant was identified in the literature in 4/55 probands with type 1 primary hyperoxaluria, however in three of these probands already carried two presumed pathogenic variants (Monico_2007_PMID:17460142). The variant was also found in two other cases of type 1 primary hyperoxaluria but was found on the same allele as the c.33_34ins variant (Coulter-Mackie_2005_PMID:15963748). The variant was identified in dbSNP (ID: rs140992177), ClinVar (classified as benign by EGL Genetic Diagnostics and as uncertain significance by Clinical Biochemistry Laboratory, Health Services Laboratory) and LOVD 3.0 (classified as likely pathogenic). The variant was identified in control databases in 510 of 282628 chromosomes at a frequency of 0.001804 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 380 of 129022 chromosomes (freq: 0.002945), South Asian in 71 of 30608 chromosomes (freq: 0.00232), Other in 11 of 7222 chromosomes (freq: 0.001523), European (Finnish) in 16 of 25118 chromosomes (freq: 0.000637), Latino in 16 of 35412 chromosomes (freq: 0.000452), African in 11 of 24942 chromosomes (freq: 0.000441), Ashkenazi Jewish in 3 of 10360 chromosomes (freq: 0.00029), and East Asian in 2 of 19944 chromosomes (freq: 0.0001). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ile279 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis of alanine:glyoxylate aminotransferase activity was not found to be affected with the p.I279T variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
AGXT-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 17, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at