rs34885252

chr2-240868930-A-G

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.65A>G(p.Asn22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,613,066 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (284 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: -0.240

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000030.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016427934).
• BP6: Variant 2-240868930-A-G is Benign according to our data. Variant chr2-240868930-A-G is described in ClinVar as [Benign]. Clinvar id is 204020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.65A>G	p.Asn22Ser	missense_variant	1/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.65A>G	p.Asn22Ser	missense_variant	1/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.85A>G		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3730 AN: 151972 Hom.: 131 Cov.: 33

Gnomad AFR AF: 0.0713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0718

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000824

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0167 AC: 4136 AN: 248228 Hom.: 127 AF XY: 0.0158 AC XY: 2123 AN XY: 134772

Gnomad AFR exome AF: 0.0719

Gnomad AMR exome AF: 0.00825

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.0869

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00869

GnomAD4 exome AF: 0.00674 AC: 9842 AN: 1460976 Hom.: 284 Cov.: 34 AF XY: 0.00710 AC XY: 5161 AN XY: 726788

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.00836

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.0772

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.000647

Gnomad4 NFE exome AF: 0.000676

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0246 AC: 3738 AN: 152090 Hom.: 131 Cov.: 33 AF XY: 0.0241 AC XY: 1795 AN XY: 74378

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0717

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.000824

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00888 Hom.: 39

Bravo AF: 0.0279

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0179 AC: 2175

Asia WGS AF: 0.0410 AC: 143 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 17, 2019	- -
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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 28969594) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.0030
Dann	Benign	0.26
DEOGEN2	Benign	0.077	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.27	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.22
Sift	Benign	0.91	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.029
ClinPred		0.00096	T
GERP RS		-8.8
Varity_R		0.043
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34885252; hg19: chr2-241808347; COSMIC: COSV56753306; COSMIC: COSV56753306;