rs34664134

chr2-240873044-G-Achr2-240873044-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000030.3(AGXT):c.590G>A(p.Arg197Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,450 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R197R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (184 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.08

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000030.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.003585279).
• BP6: Variant 2-240873044-G-A is Benign according to our data. Variant chr2-240873044-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240873044-G-A is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.590G>A	p.Arg197Gln	missense_variant	5/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.590G>A	p.Arg197Gln	missense_variant	5/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.610G>A		non_coding_transcript_exon_variant	5/5	2
AGXT	ENST00000476698.1	n.327G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152144 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0723

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.0112 AC: 2796 AN: 249144 Hom.: 91 AF XY: 0.0119 AC XY: 1603 AN XY: 134832

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0866

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.000913

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00457 AC: 6681 AN: 1461188 Hom.: 184 Cov.: 31 AF XY: 0.00528 AC XY: 3839 AN XY: 726962

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0767

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.000678

Gnomad4 NFE exome AF: 0.000585

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152262 Hom.: 23 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74438

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0723

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00326 Hom.: 14

Bravo AF: 0.00416

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0114 AC: 1382

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Dec 01, 2023	Found in cis with c.557C>T in two unrelated individuals. ACMG:BS1 BS2 BP6 -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	This variant is associated with the following publications: (PMID: 20981092, 24205397, 21228398, 19245173, 27884173, 28906061, 30341509, 33457257) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 24, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.63
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N
REVEL	Uncertain	0.36
Sift	Benign	0.98	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.076
MPC		0.035
ClinPred		0.019	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.44

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: rs34664134; hg19: chr2-241812461; COSMIC: COSV56756234; COSMIC: COSV56756234;