chr2-240876003-A-G

Variant names:

• chr2-240876003-A-G
• rs180177280
• NM_000030.3:c.845A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000030.3(AGXT):​c.845A>G​(p.Gln282Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q282H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGXT NM_000030.3 missense, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.98
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000030.3
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.845A>G	p.Gln282Arg	missense splice_region	Exon 8 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.845A>G	p.Gln282Arg	missense splice_region	Exon 8 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.845A>G	p.Gln282Arg	missense	Exon 8 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.845A>G	p.Gln282Arg	missense	Exon 8 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.54
Sift	Benign	0.047	D
Sift4G	Uncertain	0.052	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.90		Gain of MoRF binding (P = 0.0435)
MVP		0.89
MPC		0.034
ClinPred		0.23	T
GERP RS		4.9
Varity_R		0.29
gMVP		0.87
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
Splicevardb		2.0
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs180177280; hg19: chr2-241815420;