rs140992177

Positions:

chr2-240875994-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0030 ( 10 hom. )

Consequence

AGXT
NM_000030.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 5.19

Variant links:

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 links:

AGXT (HGNC:):

AGXT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

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 id is 198686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 2138 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3 linkuse as main transcript	c.836T>C	p.Ile279Thr	missense_variant	8/11	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 linkuse as main transcript	c.836T>C	p.Ile279Thr	missense_variant	8/11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000476698.1 linkuse as main transcript	n.488T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

269

AN:

152160

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00182

AC:

457

AN:

251244

Hom.:

AF XY:

0.00191

AC XY:

260

AN XY:

135856

show subpopulations

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 SAS exome

AF:

0.00232

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.:

Cov.:

AF XY:

0.00294

AC XY:

2138

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00230

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.00358

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00177

AC:

269

AN:

152278

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00328

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00260

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00185

AC:

225

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Dec 23, 2023	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) -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 25, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 08, 2021	- -

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 07, 2024	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2022	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. -

AGXT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2021

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

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.10

MutationAssessor

Pathogenic

2.9

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.79

Vest4

0.85

MVP

0.89

MPC

0.17

ClinPred

0.075

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over