rs140992177

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:2 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: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.836T>C	p.Ile279Thr	missense_variant	Exon 8 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.836T>C	p.Ile279Thr	missense_variant	Exon 8 of 11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000476698.1	n.488T>C		non_coding_transcript_exon_variant	Exon 4 of 4	5

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:4

Apr 25, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been confirmed to be pathogenic in vivo when expressed on the background of the minor allele (AGXT c.32C>T)(PMID:19479957) but, when expressed on the major allele (AGXT c.32C=), it has normal activity in vitro (PID:15963748). Interpretation therefore requires knowledge of the haplotype. ACMG for expression on minor allele:PS3 PM2 PM3 PP3 PP4 BP6 (Pathogenic) ACMG for expression on major allele:PM2 PP3 BS3 BP2 BP6 (likely benign) -

not provided Uncertain:1 Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AGXT p.Ile279Thr variant was identified in the literature in 4/55 probands with type 1 primary hyperoxaluria, however in three of these probands already carried two presumed pathogenic variants (Monico_2007_PMID:17460142). The variant was also found in two other cases of type 1 primary hyperoxaluria but was found on the same allele as the c.33_34ins variant (Coulter-Mackie_2005_PMID:15963748). The variant was identified in dbSNP (ID: rs140992177), ClinVar (classified as benign by EGL Genetic Diagnostics and as uncertain significance by Clinical Biochemistry Laboratory, Health Services Laboratory) and LOVD 3.0 (classified as likely pathogenic). The variant was identified in control databases in 510 of 282628 chromosomes at a frequency of 0.001804 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 380 of 129022 chromosomes (freq: 0.002945), South Asian in 71 of 30608 chromosomes (freq: 0.00232), Other in 11 of 7222 chromosomes (freq: 0.001523), European (Finnish) in 16 of 25118 chromosomes (freq: 0.000637), Latino in 16 of 35412 chromosomes (freq: 0.000452), African in 11 of 24942 chromosomes (freq: 0.000441), Ashkenazi Jewish in 3 of 10360 chromosomes (freq: 0.00029), and East Asian in 2 of 19944 chromosomes (freq: 0.0001). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ile279 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional analysis of alanine:glyoxylate aminotransferase activity was not found to be affected with the p.I279T variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGXT c.836T>C (p.Ile279Thr) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 251244 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.836T>C has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 without strong evidence of causality (e.g. Coulter-Mackie_2005, Monico_2007, Hoyer-Kuhn_2014, Mandrile_2014, Hopp_2015). Importantly, co-occurrences of the variant in cis with known pathogenic variants in at least 5 compound heterozygous individuals have been reported (Coulter-Mackie_2005, Monico_2007), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant has essentially normal enzymatic activity (Coulter-Mackie_2005). Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AGXT-related disorder Benign:1

Feb 17, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;