2-240875891-A-G

Variant names:

• chr2-240875891-A-G
• rs12464426
• NM_000030.3:c.777-44A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000030.3(AGXT):​c.777-44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 1,599,832 control chromosomes in the GnomAD database, including 438,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (47651 hom., cov: 34)
  • Exomes 𝑓: 0.73 (391003 hom.)
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -5.24
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-240875891-A-G is Benign according to our data. Variant chr2-240875891-A-G is described in ClinVar as [Benign]. Clinvar id is 204049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.777-44A>G		intron_variant	Intron 7 of 10	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.777-44A>G		intron_variant	Intron 7 of 10	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000476698.1	n.429-44A>G		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119110 AN: 151996 Hom.: 47604 Cov.: 34

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.748

GnomAD2 exomes AF: 0.716 AC: 177017 AN: 247316 AF XY: 0.712

Gnomad AFR exome AF: 0.958

Gnomad AMR exome AF: 0.577

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.769

Gnomad FIN exome AF: 0.744

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.722

GnomAD4 exome AF: 0.733 AC: 1060802 AN: 1447720 Hom.: 391003 Cov.: 32 AF XY: 0.729 AC XY: 525662 AN XY: 720890

African (AFR) AF: 0.958 AC: 31771 AN: 33168

American (AMR) AF: 0.589 AC: 26222 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 19089 AN: 26044

East Asian (EAS) AF: 0.741 AC: 29347 AN: 39610

South Asian (SAS) AF: 0.628 AC: 53909 AN: 85776

European-Finnish (FIN) AF: 0.742 AC: 39547 AN: 53290

Middle Eastern (MID) AF: 0.681 AC: 3905 AN: 5734

European-Non Finnish (NFE) AF: 0.739 AC: 812471 AN: 1099652

Other (OTH) AF: 0.743 AC: 44541 AN: 59952

GnomAD4 genome AF: 0.784 AC: 119197 AN: 152112 Hom.: 47651 Cov.: 34 AF XY: 0.780 AC XY: 57965 AN XY: 74330

African (AFR) AF: 0.949 AC: 39433 AN: 41562

American (AMR) AF: 0.666 AC: 10169 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 2519 AN: 3468

East Asian (EAS) AF: 0.751 AC: 3872 AN: 5154

South Asian (SAS) AF: 0.625 AC: 3011 AN: 4818

European-Finnish (FIN) AF: 0.748 AC: 7906 AN: 10568

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.734 AC: 49885 AN: 67952

Other (OTH) AF: 0.741 AC: 1566 AN: 2112

Alfa AF: 0.753 Hom.: 8025

Bravo AF: 0.785

Asia WGS AF: 0.690 AC: 2403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Benign:2

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.28
DANN	Benign	0.069
PhyloP100		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs12464426; hg19: chr2-241815308; COSMIC: COSV56755419; COSMIC: COSV56755419;