chr2-240878862-C-A

Variant names:

• chr2-240878862-C-A
• rs4273214
• NM_000030.3:c.*41C>A

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.*41C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,530,324 control chromosomes in the GnomAD database, including 108,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8132 hom., cov: 33)
  • Exomes 𝑓: 0.38 (100525 hom.)
• Consequence: AGXT NM_000030.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -2.35
• Publications: 17 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=-0.87).
• BP6: Variant 2-240878862-C-A is Benign according to our data. Variant chr2-240878862-C-A is described in ClinVar as Benign. ClinVar VariationId is 204063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.*41C>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.*41C>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000470255.1	n.998C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46763 AN: 152020 Hom.: 8136 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.303

GnomAD2 exomes AF: 0.332 AC: 52992 AN: 159740 AF XY: 0.338

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.377 AC: 520050 AN: 1378184 Hom.: 100525 Cov.: 26 AF XY: 0.377 AC XY: 256909 AN XY: 682282

African (AFR) AF: 0.144 AC: 4580 AN: 31724

American (AMR) AF: 0.252 AC: 9073 AN: 36066

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 7279 AN: 25048

East Asian (EAS) AF: 0.240 AC: 8842 AN: 36850

South Asian (SAS) AF: 0.302 AC: 23910 AN: 79254

European-Finnish (FIN) AF: 0.418 AC: 18169 AN: 43514

Middle Eastern (MID) AF: 0.287 AC: 1627 AN: 5666

European-Non Finnish (NFE) AF: 0.401 AC: 426332 AN: 1062480

Other (OTH) AF: 0.351 AC: 20238 AN: 57582

GnomAD4 genome AF: 0.307 AC: 46762 AN: 152140 Hom.: 8132 Cov.: 33 AF XY: 0.306 AC XY: 22731 AN XY: 74366

African (AFR) AF: 0.152 AC: 6322 AN: 41528

American (AMR) AF: 0.262 AC: 4012 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3470

East Asian (EAS) AF: 0.254 AC: 1310 AN: 5154

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4824

European-Finnish (FIN) AF: 0.430 AC: 4552 AN: 10590

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27141 AN: 67954

Other (OTH) AF: 0.303 AC: 640 AN: 2114

Alfa AF: 0.358 Hom.: 12091

Bravo AF: 0.292

Asia WGS AF: 0.284 AC: 991 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.87
CADD	Benign	1.0
DANN	Benign	0.49
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs4273214; hg19: chr2-241818279; COSMIC: COSV56755073; COSMIC: COSV56755073;