5-35012979-C-T

Position:

• chr5-35012979-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031900.4(AGXT2):​c.1163G>A​(p.Cys388Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGXT2 NM_031900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

Genes affected

AGXT2 (HGNC:14412): (alanine--glyoxylate aminotransferase 2) The protein encoded by this gene is a class III pyridoxal-phosphate-dependent mitochondrial aminotransferase. It catalyzes the conversion of glyoxylate to glycine using L-alanine as the amino donor. It is an important regulator of methylarginines and is involved in the control of blood pressure in kidney. Polymorphisms in this gene affect methylarginine and beta-aminoisobutyrate metabolism, and are associated with carotid atherosclerosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

AGXT2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT2	NM_031900.4	c.1163G>A	p.Cys388Tyr	missense_variant	11/14	ENST00000231420.11	NP_114106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT2	ENST00000231420.11	c.1163G>A	p.Cys388Tyr	missense_variant	11/14	1	NM_031900.4	ENSP00000231420.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.1163G>A (p.C388Y) alteration is located in exon 11 (coding exon 11) of the AGXT2 gene. This alteration results from a G to A substitution at nucleotide position 1163, causing the cysteine (C) at amino acid position 388 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.87		Loss of catalytic residue at M386 (P = 7e-04);
MVP		0.40
MPC		0.54
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.98

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: rs1766700789; hg19: chr5-35013084;