rs33958047

Positions:

• chr2-240874036-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000030.3(AGXT):​c.654G>A​(p.Ser218Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,208 control chromosomes in the GnomAD database, including 9,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1383 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8611 hom.)
• Consequence: AGXT NM_000030.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -5.20

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]

AGXT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-240874036-G-A is Benign according to our data. Variant chr2-240874036-G-A is described in ClinVar as [Benign]. Clinvar id is 198034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.654G>A	p.Ser218Ser	synonymous_variant	6/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.654G>A	p.Ser218Ser	synonymous_variant	6/11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000476698.1	n.332+987G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19225 AN: 152044 Hom.: 1382 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.105 AC: 26405 AN: 251006 Hom.: 1580 AF XY: 0.106 AC XY: 14335 AN XY: 135702

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0514

Gnomad ASJ exome AF: 0.0930

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.123

Gnomad FIN exome AF: 0.0887

Gnomad NFE exome AF: 0.0987

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.107 AC: 155817 AN: 1461046 Hom.: 8611 Cov.: 33 AF XY: 0.107 AC XY: 77810 AN XY: 726828

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.0950

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0884

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.126 AC: 19240 AN: 152162 Hom.: 1383 Cov.: 33 AF XY: 0.127 AC XY: 9452 AN XY: 74386

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.0725

Gnomad4 ASJ AF: 0.0928

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0879

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.103

Alfa AF: 0.111 Hom.: 461

Bravo AF: 0.128

Asia WGS AF: 0.165 AC: 572 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.101

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.068
DANN	Benign	0.48

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: rs33958047; hg19: chr2-241813453; COSMIC: COSV56753400; COSMIC: COSV56753400;