rs58120546

Variant names:

• chr2-240869074-T-A
• rs58120546
• NM_000030.3:c.165+44T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000030.3(AGXT):​c.165+44T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,385,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.0150
• Publications: 2 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

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.165+44T>A		intron_variant	Intron 1 of 10	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.165+44T>A		intron_variant	Intron 1 of 10	1	NM_000030.3	ENSP00000302620.3

Frequencies

GnomAD3 genomes AF: 0.000341 AC: 51 AN: 149574 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000374

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00102 AC: 1412 AN: 1385060 Hom.: 1 Cov.: 31 AF XY: 0.00103 AC XY: 713 AN XY: 691450

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000943 AC: 31 AN: 32886

American (AMR) AF: 0.000294 AC: 13 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 28 AN: 25160

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39598

South Asian (SAS) AF: 0.000695 AC: 59 AN: 84950

European-Finnish (FIN) AF: 0.00391 AC: 190 AN: 48592

Middle Eastern (MID) AF: 0.000711 AC: 4 AN: 5626

European-Non Finnish (NFE) AF: 0.000995 AC: 1041 AN: 1045908

Other (OTH) AF: 0.000585 AC: 34 AN: 58070

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000341 AC: 51 AN: 149574 Hom.: 0 Cov.: 31 AF XY: 0.000398 AC XY: 29 AN XY: 72874

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000367 AC: 15 AN: 40896

American (AMR) AF: 0.000332 AC: 5 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00106 AC: 5 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000374 AC: 25 AN: 66860

Other (OTH) AF: 0.00 AC: 0 AN: 2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0816 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary hyperoxaluria, type I Uncertain:1

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.68
PhyloP100		-0.015
Mutation Taster		=100/0	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: rs58120546; hg19: chr2-241808491; COSMIC: COSV56754032; COSMIC: COSV56754032;