2-240868891-C-A

Variant names:

• chr2-240868891-C-A
• rs115014558
• NM_000030.3:c.26C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 16/21 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
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• alanine glyoxylate aminotransferase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• primary hyperoxaluria type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 8 uncertain in NM_000030.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 130 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: -0.26789 (below the threshold of 3.09). Trascript score misZ: -0.48778 (below the threshold of 3.09). GenCC associations: The gene is linked to alanine glyoxylate aminotransferase deficiency, primary hyperoxaluria type 1.
• 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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000030.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.26C>A	p.Thr9Asn	missense	Exon 1 of 11	NP_000021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.26C>A	p.Thr9Asn	missense	Exon 1 of 11	ENSP00000302620.3
	AGXT	ENST00000908235.1		c.26C>A	p.Thr9Asn	missense	Exon 1 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.26C>A	p.Thr9Asn	missense	Exon 1 of 12	ENSP00000578295.1

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

GnomAD2 exomes AF: 0.00919 AC: 2204 AN: 239930 AF XY: 0.00945

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 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

African (AFR) AF: 0.00132 AC: 44 AN: 33434

American (AMR) AF: 0.00624 AC: 278 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 336 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00669 AC: 575 AN: 85978

European-Finnish (FIN) AF: 0.0133 AC: 695 AN: 52432

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5760

European-Non Finnish (NFE) AF: 0.00961 AC: 10685 AN: 1111424

Other (OTH) AF: 0.00879 AC: 530 AN: 60322

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

African (AFR) AF: 0.00190 AC: 79 AN: 41504

American (AMR) AF: 0.00445 AC: 68 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4812

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 711 AN: 67944

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00913 Hom.: 22

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	3	Primary hyperoxaluria, type I (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.78
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
PromoterAI		0.0020	Neutral
Varity_R		0.11
gMVP		0.73
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs115014558; hg19: chr2-241808308;