chr2-240869043-G-GTCACTCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCC

Position:

• chr2-240869043-G-GTCACTCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000030.3(AGXT):​c.165+19_166-48dupCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCCTCACT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -1.53

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-240869043-G-GTCACTCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCC is Benign according to our data. Variant chr2-240869043-G-GTCACTCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCC is described in ClinVar as [Likely_benign]. Clinvar id is 204024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.165+19_166-48dupCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCCTCACT		intron_variant		ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.165+19_166-48dupCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCCTCACT		intron_variant		1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000472436.1	n.185+19_186-48dupCGGGGGGCCTGGGTCTCACCCATGTTCCCACCCACAGATCGTGGACGAGGGAAGGGGGTCACTGCCTCCTCACT		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Biochemistry Laboratory, Health Services Laboratory

Nov 27, 2014

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 11, 2017

Variant summary: The AGXT c.165+19_165+92dup74 variant involves the duplication of 74 nucleotides in the first intron of the AGXT gene. 5/5 splice prediction tools predict no significant impact on the splice donor site. This variant was found in 4/221932 control chromosomes from gnomAD at a frequency of 0.00001802, however this frequency may not be accurate since a duplication of this size may not be captured properly by gnomAD/ExAC and similar overlapping duplications are present at low frequencies. This variant is widely reported as a polymorphism found in general population in literature and generally forms a haplotype with other two polymorphisms P11L and I340M (Purdue_1991, Coulter-Mackie_2003, Wang_2016). Its reported allele frequencies in multiple ethnic backgrounds from publications are 6.5% in European controls (Purdue_1991), 9% in South African controls (Coulter-Mackie_2003) and 3% in Chinese controls (Wang_2016), however, all control cohorts in these studies are small with less than or equal to 200 control chromosomes. This variant or its haplotypic form has been reported in the same chromosome (in cis) with known pathogenic or likely pathogenic variants, such as G170R, A112D, and R333X (Coulter-Mackie_2003, Wang_2016), further supporting benign outcome. In addition, this variant is unlikely to affect splicing because stable AGT mRNA produced was derived from the haplotype comprising this variant, p.Pro11Leu and p.Ile340Met (Purdue_1991). Taken together, this variant is classified likely benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177174; hg19: chr2-241808460;