2-240868867-TG-AT

Variant names:

• chr2-240868867-TG-AT
• rs180177194
• NM_000030.3:c.2_3delTGinsAT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Supporting PM2 PP5_Very_Strong

The NM_000030.3(AGXT):​c.2_3delTGinsAT​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGXT NM_000030.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.14

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 11 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 111 CDS bases. Genomic position: 240868976. Lost 0.094 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-240868867-TG-AT is Pathogenic according to our data. Variant chr2-240868867-TG-AT is described in ClinVar as [Pathogenic]. Clinvar id is 204172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.2_3delTGinsAT	p.Met1?	start_lost		ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.2_3delTGinsAT	p.Met1?	start_lost		1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000472436.1	n.22_23delTGinsAT		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:2

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

Feb 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the AGXT mRNA. The next in-frame methionine is located at codon 38. Experimental studies have shown that disruption of the initiator codon affects AGXT function (PMID: 17495019). This variant disrupts the p.Arg36 amino acid residue in AGXT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29110180, 30341509). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of the initiator codon has been observed in individuals with hyperoxaluria (PMID: 15365967, 29456205). ClinVar contains an entry for this variant (Variation ID: 204172). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177194; hg19: chr2-241808284;