NM_000030.3:c.883G>A

Variant names:

• chr2-240877573-G-A
• rs13408961
• NM_000030.3:c.883G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000030.3(AGXT):​c.883G>A​(p.Ala295Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,550,806 control chromosomes in the GnomAD database, including 244 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. A295A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (132 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (112 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: 0.00100
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -17 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, 9 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=0.0019549727).
• BP6: Variant 2-240877573-G-A is Benign according to our data. Variant chr2-240877573-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 204056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.883G>A	p.Ala295Thr	missense	Exon 9 of 11	NP_000021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.883G>A	p.Ala295Thr	missense	Exon 9 of 11	ENSP00000302620.3
	AGXT	ENST00000470255.1	TSL:2	n.661G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3479 AN: 152214 Hom.: 132 Cov.: 34

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00719

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00667 AC: 1025 AN: 153624 AF XY: 0.00515

Gnomad AFR exome AF: 0.0838

Gnomad AMR exome AF: 0.00340

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.000267

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.00436

GnomAD4 exome AF: 0.00301 AC: 4216 AN: 1398474 Hom.: 112 Cov.: 31 AF XY: 0.00273 AC XY: 1886 AN XY: 689798

African (AFR) AF: 0.0813 AC: 2570 AN: 31598

American (AMR) AF: 0.00409 AC: 146 AN: 35676

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 548 AN: 25160

East Asian (EAS) AF: 0.000196 AC: 7 AN: 35744

South Asian (SAS) AF: 0.000202 AC: 16 AN: 79222

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48520

Middle Eastern (MID) AF: 0.00316 AC: 18 AN: 5696

European-Non Finnish (NFE) AF: 0.000472 AC: 509 AN: 1078866

Other (OTH) AF: 0.00691 AC: 401 AN: 57992

GnomAD4 genome AF: 0.0229 AC: 3492 AN: 152332 Hom.: 132 Cov.: 34 AF XY: 0.0221 AC XY: 1644 AN XY: 74490

African (AFR) AF: 0.0776 AC: 3224 AN: 41566

American (AMR) AF: 0.00718 AC: 110 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68024

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.00650 Hom.: 39

Bravo AF: 0.0261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0665 AC: 273

ESP6500EA AF: 0.00138 AC: 11

ExAC AF: 0.00498 AC: 377

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	3	Primary hyperoxaluria, type I (5)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.85
DANN	Benign	0.91
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.0010
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Benign	0.26	T
Sift4G	Benign	0.25	T
Polyphen		0.0050	B
Vest4		0.15
MVP		0.40
MPC		0.033
ClinPred		0.0073	T
GERP RS		-6.1
Varity_R		0.19
gMVP		0.85
Mutation Taster		=90/10	polymorphism (auto)

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: rs13408961; hg19: chr2-241816990; COSMIC: COSV56754979; COSMIC: COSV56754979;