rs180177155

Variant names:

• chr2-240878086-T-A
• rs180177155
• NM_000030.3:c.1007T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-240878086-T-A
• chr2-240878086-T-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000030.3(AGXT):​c.1007T>A​(p.Val336Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V336I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0950
• Publications: 7 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 2-240878086-T-A is Pathogenic according to our data. Variant chr2-240878086-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 204143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1007T>A	p.Val336Asp	missense	Exon 10 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.1007T>A	p.Val336Asp	missense	Exon 10 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.1280T>A	p.Val427Asp	missense	Exon 11 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.1196T>A	p.Val399Asp	missense	Exon 11 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250634 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461056 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726834

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.095
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.013	D
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.63
MutPred		0.91		Loss of stability (P = 0.2082)
MVP		0.90
MPC		0.20
ClinPred		0.53	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.95
Mutation Taster		=72/28	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180177155; hg19: chr2-241817503;