2-240868891-C-A

Position:

• chr2-240868891-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000030.3(AGXT):​c.26C>A​(p.Thr9Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,611,766 control chromosomes in the GnomAD database, including 80 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T9T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (74 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 0.775

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 2 benign, 5 uncertain in NM_000030.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.007460147).
• BP6: Variant 2-240868891-C-A is Benign according to our data. Variant chr2-240868891-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 204016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00709 (1079/152088) while in subpopulation NFE AF= 0.0105 (711/67944). AF 95% confidence interval is 0.00983. There are 6 homozygotes in gnomad4. There are 504 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.26C>A	p.Thr9Asn	missense_variant	1/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.26C>A	p.Thr9Asn	missense_variant	1/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.46C>A		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1080 AN: 151974 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00919 AC: 2204 AN: 239930 Hom.: 18 AF XY: 0.00945 AC XY: 1233 AN XY: 130504

Gnomad AFR exome AF: 0.00157

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00595

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.00906 AC: 13227 AN: 1459678 Hom.: 74 Cov.: 31 AF XY: 0.00908 AC XY: 6596 AN XY: 726058

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00669

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.00961

Gnomad4 OTH exome AF: 0.00879

GnomAD4 genome AF: 0.00709 AC: 1079 AN: 152088 Hom.: 6 Cov.: 33 AF XY: 0.00678 AC XY: 504 AN XY: 74354

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00901 Hom.: 12

Bravo AF: 0.00649

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00968 AC: 1173

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	in vitro	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AGXT: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	This variant is associated with the following publications: (PMID: 28969594, 27884173, 15849466, 21228398, 20981092, 17495019) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.9
DANN	Benign	0.84
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.26
Sift	Benign	0.045	D
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.69
MVP		0.46
MPC		0.036
ClinPred		0.0012	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.73

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: rs115014558; hg19: chr2-241808308;