NM_000030.3:c.836T>C

Variant names:

• chr2-240875994-T-C
• rs140992177
• NM_000030.3:c.836T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_000030.3(AGXT):​c.836T>C​(p.Ile279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0029 in 1,614,098 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I279M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 5.19
• Publications: 11 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000030.3
• 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=0.13906038).
• BP6: Variant 2-240875994-T-C is Benign according to our data. Variant chr2-240875994-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198686.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00302 (4408/1461820) while in subpopulation NFE AF = 0.00358 (3982/1111972). AF 95% confidence interval is 0.00349. There are 10 homozygotes in GnomAdExome4. There are 2138 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.836T>C	p.Ile279Thr	missense	Exon 8 of 11	NP_000021.1	P21549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.836T>C	p.Ile279Thr	missense	Exon 8 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.836T>C	p.Ile279Thr	missense	Exon 8 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.836T>C	p.Ile279Thr	missense	Exon 8 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152160 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00182 AC: 457 AN: 251244 AF XY: 0.00191

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00302 AC: 4408 AN: 1461820 Hom.: 10 Cov.: 35 AF XY: 0.00294 AC XY: 2138 AN XY: 727208

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86246

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53408

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00358 AC: 3982 AN: 1111972

Other (OTH) AF: 0.00232 AC: 140 AN: 60396

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152278 Hom.: 1 Cov.: 34 AF XY: 0.00153 AC XY: 114 AN XY: 74458

African (AFR) AF: 0.000313 AC: 13 AN: 41564

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00168

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	Primary hyperoxaluria, type I (6)
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	AGXT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.2
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.85
MVP		0.89
MPC		0.17
ClinPred		0.075	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.92
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs140992177; hg19: chr2-241815411; COSMIC: COSV56754765; COSMIC: COSV56754765;