chr2-240878086-T-A

Variant names:

• chr2-240878086-T-A
• rs180177155
• NM_000030.3:c.1007T>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000030.3(AGXT):​c.1007T>A​(p.Val336Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,056 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V336I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0950

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

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 130 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: -0.26789 (below the threshold of 3.09). Trascript score misZ: -0.48778 (below the threshold of 3.09). GenCC associations: The gene is linked to primary hyperoxaluria type 1, alanine glyoxylate aminotransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 2-240878086-T-A is Pathogenic according to our data. Variant chr2-240878086-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204143.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.1007T>A	p.Val336Asp	missense_variant	Exon 10 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.1007T>A	p.Val336Asp	missense_variant	Exon 10 of 11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000470255.1	n.785T>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250634 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461056 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726834

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44718

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52618

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1111992

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:3

Mar 02, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: in vitro

- -

Dec 08, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AGXT protein function. ClinVar contains an entry for this variant (Variation ID: 204143). This missense change has been observed in individuals with primary hyperoxaluria type 1 (PMID: 25629080, 34082749). This variant is present in population databases (rs180177155, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 336 of the AGXT protein (p.Val336Asp). Experimental studies have shown that this missense change affects AGXT function (PMID: 18448374, 22529745). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.013	D
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.63
MutPred		0.91		Loss of stability (P = 0.2082);
MVP		0.90
MPC		0.20
ClinPred		0.53	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.95
Mutation Taster		=72/28	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180177155; hg19: chr2-241817503;