rs180177190

Variant names:

• chr2-240869285-T-TGGA
• rs180177190
• NM_000030.3:c.283_285dupGAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_000030.3(AGXT):​c.283_285dupGAG​(p.Glu95dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P96P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AGXT NM_000030.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000030.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000030.3. Strenght limited to Supporting due to length of the change: 1aa.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.283_285dupGAG	p.Glu95dup	conservative_inframe_insertion	Exon 2 of 11	NP_000021.1	P21549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.283_285dupGAG	p.Glu95dup	conservative_inframe_insertion	Exon 2 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.283_285dupGAG	p.Glu95dup	conservative_inframe_insertion	Exon 2 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.283_285dupGAG	p.Glu95dup	conservative_inframe_insertion	Exon 2 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461256 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726912

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
1	-	-	Primary hyperoxaluria, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs180177190; hg19: chr2-241808702;