NM_000030.3:c.126dupG

Variant names:

• chr2-240868985-C-CG
• rs180177171
• NM_000030.3:c.126dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000030.3(AGXT):​c.126dupG​(p.Leu43AlafsTer125) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000013 in 1,534,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000079 (0 hom., cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGXT NM_000030.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.81
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-240868985-C-CG is Pathogenic according to our data. Variant chr2-240868985-C-CG is described in ClinVar as Pathogenic. ClinVar VariationId is 554314.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000030.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.126dupG	p.Leu43AlafsTer125	frameshift	Exon 1 of 11	NP_000021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.126dupG	p.Leu43AlafsTer125	frameshift	Exon 1 of 11	ENSP00000302620.3
	AGXT	ENST00000472436.1	TSL:2	n.146dupG		non_coding_transcript_exon	Exon 1 of 5
	ENSG00000297735	ENST00000750632.1		n.237+1247dupC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000794 AC: 1 AN: 125882 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408406 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 700096

African (AFR) AF: 0.00 AC: 0 AN: 31940

American (AMR) AF: 0.00 AC: 0 AN: 43304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24476

East Asian (EAS) AF: 0.00 AC: 0 AN: 37352

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076468

Other (OTH) AF: 0.00 AC: 0 AN: 57278

GnomAD4 genome AF: 0.00000794 AC: 1 AN: 125882 Hom.: 0 Cov.: 34 AF XY: 0.0000163 AC XY: 1 AN XY: 61446

African (AFR) AF: 0.00 AC: 0 AN: 35068

American (AMR) AF: 0.0000765 AC: 1 AN: 13064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2928

East Asian (EAS) AF: 0.00 AC: 0 AN: 4644

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 55666

Other (OTH) AF: 0.00 AC: 0 AN: 1660

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:2

Oct 27, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

ACMG:PVS1 PM2 PM3 PP4

Oct 16, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs180177171; hg19: chr2-241808402; COSMIC: COSV56754812; COSMIC: COSV56754812;