rs180177264

chr2-240875185-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000030.3(AGXT):c.757T>C(p.Cys253Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,461,224 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C253C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.46

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000030.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 2-240875185-T-C is Pathogenic according to our data. Variant chr2-240875185-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.757T>C	p.Cys253Arg	missense_variant	7/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.757T>C	p.Cys253Arg	missense_variant	7/11	1	NM_000030.3	P1
AGXT	ENST00000476698.1	n.409T>C		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461224 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726964

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:2

Pathogenic, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 02, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AGXT function (PMID: 17495019, 22923379, 24718375). 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) performed at Invitae indicates that this missense variant is expected to disrupt AGXT protein function. ClinVar contains an entry for this variant (Variation ID: 204126). This missense change has been observed in individual(s) with Primary Hyperoxaluria Type 1 (PMID: 15849466, 17495019). This variant is present in population databases (rs180177264, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 253 of the AGXT protein (p.Cys253Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.80		Gain of disorder (P = 0.0106);
MVP		0.96
MPC		0.30
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs180177264; hg19: chr2-241814602;