rs180177223

Positions:

• chr2-240871382-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000030.3(AGXT):​c.457T>G​(p.Leu153Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.855

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000030.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 2-240871382-T-G is Pathogenic according to our data. Variant chr2-240871382-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 204102.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.457T>G	p.Leu153Val	missense_variant	4/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.457T>G	p.Leu153Val	missense_variant	4/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.477T>G		non_coding_transcript_exon_variant	4/5	2
AGXT	ENST00000476698.1	n.194T>G		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro

Clinical Biochemistry Laboratory, Health Services Laboratory

Nov 27, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.89	L
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.53
Sift	Benign	0.32	T
Sift4G	Benign	0.33	T
Polyphen		0.0050	B
Vest4		0.85
MutPred		0.78		Loss of stability (P = 0.1467);
MVP		0.75
MPC		0.035
ClinPred		0.19	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177223; hg19: chr2-241810799;