rs117195882

chr2-240873011-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000030.3(AGXT):c.557C>T(p.Ala186Val) variant causes a missense change. The variant allele was found at a frequency of 0.00453 in 1,613,864 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (185 hom.)
• Consequence: AGXT NM_000030.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000030.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.01129064).
• BP6: Variant 2-240873011-C-T is Benign according to our data. Variant chr2-240873011-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240873011-C-T is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.557C>T	p.Ala186Val	missense_variant	5/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.557C>T	p.Ala186Val	missense_variant	5/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.577C>T		non_coding_transcript_exon_variant	5/5	2
AGXT	ENST00000476698.1	n.294C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152162 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.0113 AC: 2811 AN: 249728 Hom.: 92 AF XY: 0.0119 AC XY: 1613 AN XY: 135090

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0868

Gnomad SAS exome AF: 0.0292

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000883

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00457 AC: 6684 AN: 1461584 Hom.: 185 Cov.: 31 AF XY: 0.00527 AC XY: 3835 AN XY: 727114

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0768

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.000694

Gnomad4 NFE exome AF: 0.000564

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152280 Hom.: 22 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74440

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0719

Gnomad4 SAS AF: 0.0296

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000916 Hom.: 1

Bravo AF: 0.00413

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0114 AC: 1384

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Oct 27, 2023	Found in cis with c.590G>A in 2 unrelated individuals. ACMG:PM2 PP3 BP2 BP5 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination 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	Apr 16, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 15, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2020	This variant is associated with the following publications: (PMID: 30341509, 33457257) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 24, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.61
Sift	Benign	0.089	T
Sift4G	Uncertain	0.040	D
Polyphen		0.45	B
Vest4		0.15
MPC		0.055
ClinPred		0.069	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
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

Other links and lift over

dbSNP: rs117195882; hg19: chr2-241812428; COSMIC: COSV56753250; COSMIC: COSV56753250;