NM_000030.3:c.145A>C

Variant names:

• chr2-240869010-A-C
• rs74205173
• NM_000030.3:c.145A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000030.3(AGXT):​c.145A>C​(p.Met49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,596,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 1.48
• Publications: 6 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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=0.008694053).
• BP6: Variant 2-240869010-A-C is Benign according to our data. Variant chr2-240869010-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 550334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000295 (43/145780) while in subpopulation EAS AF = 0.00798 (36/4514). AF 95% confidence interval is 0.00592. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.145A>C	p.Met49Leu	missense	Exon 1 of 11	NP_000021.1	P21549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.145A>C	p.Met49Leu	missense	Exon 1 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.145A>C	p.Met49Leu	missense	Exon 1 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.145A>C	p.Met49Leu	missense	Exon 1 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 44 AN: 145688 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00819

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000498 AC: 122 AN: 245148 AF XY: 0.000390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00618

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000146 AC: 212 AN: 1450894 Hom.: 0 Cov.: 34 AF XY: 0.000158 AC XY: 114 AN XY: 721328

African (AFR) AF: 0.00 AC: 0 AN: 31744

American (AMR) AF: 0.0000450 AC: 2 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00421 AC: 150 AN: 35620

South Asian (SAS) AF: 0.000167 AC: 14 AN: 83968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52092

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5730

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111386

Other (OTH) AF: 0.000418 AC: 25 AN: 59828

GnomAD4 genome AF: 0.000295 AC: 43 AN: 145780 Hom.: 0 Cov.: 33 AF XY: 0.000267 AC XY: 19 AN XY: 71286

African (AFR) AF: 0.0000275 AC: 1 AN: 36386

American (AMR) AF: 0.0000662 AC: 1 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00798 AC: 36 AN: 4514

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67926

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000412

ExAC AF: 0.000437 AC: 53

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	13
DANN	Benign	0.50
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.84
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0060	B
Vest4		0.19
MutPred		0.71		Loss of helix (P = 0.0444)
MVP		0.63
MPC		0.032
ClinPred		0.017	T
GERP RS		3.2
PromoterAI		0.0058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.77
Mutation Taster		=69/31	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: rs74205173; hg19: chr2-241808427;