rs180177210

Positions:

• chr2-240870649-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000030.3(AGXT):​c.364C>T​(p.Arg122Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,400,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: AGXT NM_000030.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.0780

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

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 2-240870649-C-T is Pathogenic according to our data. Variant chr2-240870649-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 204097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240870649-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.364C>T	p.Arg122Ter	stop_gained	3/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.364C>T	p.Arg122Ter	stop_gained	3/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1	n.384C>T		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000628 AC: 1 AN: 159126 Hom.: 0 AF XY: 0.0000119 AC XY: 1 AN XY: 83890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000436

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1400454 Hom.: 0 Cov.: 31 AF XY: 0.00000724 AC XY: 5 AN XY: 690894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000504

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000187 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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. Clinical variability has been reported for affected relatives carrying the same pathogenic variant (GeneReviews, PMID: 35695965). (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) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported as compound heterozygous in individuals with primary hyperoxaluria type 1 (ClinVar, PMIDs: 24385516, 30341509). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (external diagnostic report). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Apr 08, 2021	This individual is heterozygous for a pathogenic variant, c.364C>T in the AGXT gene. This variant creates a premature stop codon p.(Arg122*) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has been previously reported, homozygous or compound heterozygous with other AGXT disease causing variants, in individuals with hyperoxaluria (Dulz et al 2018 PMID: 29244539; Martinez-Turrillas et al 2019 PMID: 31715429; ClinVar, accessed: 20/07/21 https://www.ncbi.nlm.nih.gov/clinvar/variation/204097/). This variant has been reported in the gnomAD v2.1.1 browser (http://gnomad.broadinstitute.org accessed: 08/04/2021) with a very low allele frequency of 0.0006% (1 out of 159,126 alleles). This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PM3_Strong). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 16, 2021	This variant is predicted to cause a premature termination of the protein and the resultant protein will likely to lack C-terminal part of the protein; this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense-mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The variant was previously reported in several individuals affected with primary hyperoxaluria [PMID: 21850686, 29244539, 19479957]. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 204097). This premature translational stop signal has been observed in individuals with primary hyperoxaluria (PMID: 19479957, 21850686, 29244539). 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 sequence change creates a premature translational stop signal (p.Arg122*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.16	N
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs180177210; hg19: chr2-241810066;