5-35010047-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031900.4(AGXT2):c.1291G>A(p.Val431Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00038 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: AGXT2 NM_031900.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3231038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT2	NM_031900.4	c.1291G>A	p.Val431Ile	missense_variant	12/14	ENST00000231420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT2	ENST00000231420.11	c.1291G>A	p.Val431Ile	missense_variant	12/14	1	NM_031900.4	P1
AGXT2	ENST00000510428.1	c.1066G>A	p.Val356Ile	missense_variant	10/13	1
AGXT2	ENST00000618015.4	c.1066G>A	p.Val356Ile	missense_variant	10/12	5
AGXT2	ENST00000512135.5	n.961G>A		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

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: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251382 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.000366 AC XY: 266 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000499

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74356

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

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

Apr 08, 2022

The c.1291G>A (p.V431I) alteration is located in exon 12 (coding exon 12) of the AGXT2 gene. This alteration results from a G to A substitution at nucleotide position 1291, causing the valine (V) at amino acid position 431 to be replaced by an isoleucine (I). 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	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;.
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.98	N;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.033	D;.;D
Sift4G	Benign	0.065	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.33
MVP		0.71
MPC		0.17
ClinPred		0.12	T
GERP RS		3.9
Varity_R		0.21
gMVP		0.75

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: rs142368612; hg19: chr5-35010152;