NM_000030.3:c.31C>G

Variant names:

• chr2-240868896-C-G
• rs375712696
• NM_000030.3:c.31C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP2

The NM_000030.3(AGXT):​c.31C>G​(p.Pro11Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,612,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.92
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000030.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240868897-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.31C>G	p.Pro11Ala	missense_variant	Exon 1 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.31C>G	p.Pro11Ala	missense_variant	Exon 1 of 11	1	NM_000030.3	ENSP00000302620.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000890 AC: 22 AN: 247166 AF XY: 0.0000521

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 726676

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.000313 AC: 14 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39692

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111880

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.099
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.9
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.37		Loss of glycosylation at P11 (P = 0.0183);
MVP		0.96
MPC		0.24
ClinPred		0.75	D
GERP RS		3.5
PromoterAI		0.047	Neutral
Varity_R		0.76
gMVP		0.82
Mutation Taster		=83/17	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: rs375712696; hg19: chr2-241808313; COSMIC: COSV56755949; COSMIC: COSV56755949;