rs180749

Positions:

• chr5-35033500-G-A
• chr5-35033500-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000231420.11(AGXT2):​c.635C>T​(p.Thr212Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.976 in 1,613,754 control chromosomes in the GnomAD database, including 771,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.94 (67233 hom., cov: 31)
  • Exomes 𝑓: 0.98 (704511 hom.)
• Consequence: AGXT2 ENST00000231420.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.914

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.9576423E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT2	NM_031900.4	c.635C>T	p.Thr212Ile	missense_variant	6/14	ENST00000231420.11	NP_114106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT2	ENST00000231420.11	c.635C>T	p.Thr212Ile	missense_variant	6/14	1	NM_031900.4	ENSP00000231420	P1
AGXT2	ENST00000510428.1	c.635C>T	p.Thr212Ile	missense_variant	6/13	1		ENSP00000422799
AGXT2	ENST00000618015.4	c.635C>T	p.Thr212Ile	missense_variant	6/12	5		ENSP00000479154
AGXT2	ENST00000505542.1	n.544C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.937 AC: 142474 AN: 152092 Hom.: 67217 Cov.: 31

Gnomad AFR AF: 0.831

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.952

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.778

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.948

GnomAD3 exomes AF: 0.951 AC: 238991 AN: 251314 Hom.: 114306 AF XY: 0.954 AC XY: 129556 AN XY: 135806

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.995

Gnomad EAS exome AF: 0.788

Gnomad SAS exome AF: 0.909

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.975

GnomAD4 exome AF: 0.981 AC: 1433184 AN: 1461544 Hom.: 704511 Cov.: 50 AF XY: 0.979 AC XY: 711996 AN XY: 727124

Gnomad4 AFR exome AF: 0.825

Gnomad4 AMR exome AF: 0.936

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 0.794

Gnomad4 SAS exome AF: 0.909

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.965

GnomAD4 genome AF: 0.936 AC: 142526 AN: 152210 Hom.: 67233 Cov.: 31 AF XY: 0.935 AC XY: 69586 AN XY: 74420

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.952

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.901

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.948

Alfa AF: 0.982 Hom.: 154774

Bravo AF: 0.930

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 0.999 AC: 3849

ESP6500AA AF: 0.832 AC: 3664

ESP6500EA AF: 0.999 AC: 8589

ExAC AF: 0.949 AC: 115226

Asia WGS AF: 0.830 AC: 2887 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.096
DANN	Benign	0.80
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.031	T;T;.
MetaRNN	Benign	9.0e-7	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.2	D;.;D
REVEL	Benign	0.17
Sift	Benign	0.30	T;.;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.077
MPC		0.081
ClinPred		0.0067	T
GERP RS		-5.2
Varity_R		0.073
gMVP		0.48

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: rs180749; hg19: chr5-35033605;