chr2-240878086-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2 PM5 PP2 BP4_Moderate

The NM_000030.3(AGXT):​c.1007T>C​(p.Val336Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V336D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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=0.20561242).

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.1007T>C	p.Val336Ala	missense	Exon 10 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.1007T>C	p.Val336Ala	missense	Exon 10 of 11	ENSP00000302620.3
	AGXT	ENST00000470255.1	TSL:2	n.785T>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	13
DANN	Benign	0.45
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.095
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.53
Sift	Benign	0.59	T
Sift4G	Benign	0.66	T
Polyphen		0.020	B
Vest4		0.33
MutPred		0.57		Loss of stability (P = 0.0373)
MVP		0.66
MPC		0.044
ClinPred		0.13	T
GERP RS		1.6
Varity_R		0.37
gMVP		0.84
Mutation Taster		=74/26	polymorphism

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;