rs66494441

Positions:

• chr2-240869046-A-G
• chr2-240869046-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000030.3(AGXT):​c.165+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,609,108 control chromosomes in the GnomAD database, including 30,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2351 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27904 hom.)
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: -2.42

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-240869046-A-G is Benign according to our data. Variant chr2-240869046-A-G is described in ClinVar as [Benign]. Clinvar id is 204021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240869046-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.165+16A>G		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+16A>G		intron_variant		1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1	n.185+16A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25708 AN: 151760 Hom.: 2341 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0726

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.160 AC: 39256 AN: 244910 Hom.: 3552 AF XY: 0.163 AC XY: 21703 AN XY: 133474

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.0861

Gnomad SAS exome AF: 0.100

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.191 AC: 277793 AN: 1457230 Hom.: 27904 Cov.: 33 AF XY: 0.188 AC XY: 136241 AN XY: 724742

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0906

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.0773

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.169 AC: 25735 AN: 151878 Hom.: 2351 Cov.: 33 AF XY: 0.168 AC XY: 12463 AN XY: 74206

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0726

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.179

Alfa AF: 0.124 Hom.: 260

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2017	Variant summary: The AGXT c.165+16A>G variant involves the alteration of a non-conserved intronic nucleotide at a position not widely known to affect splicing. Mutation taster predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 19192/117856 control chromosomes (1649 homozygotes) from ExAC at a frequency of 0.1628428, which is approximately 69 times the estimated maximal expected allele frequency of a pathogenic AGXT variant (0.0023717), thus this variant is a common benign polymorphism. This variant, as a part of a haplotype, has been reported in patients with primary hyperoxaluria type 1 in whom another pathogenic variant (p.Ile244Thr) in homozygosity explained the phenotype, further supporting the benign nature (Kanoun_2013). One clinical diagnostic laboratory (via ClinVar) has classified it as benign. Taken together, this variant is classified as benign. -

Primary hyperoxaluria, type I Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Biochemistry Laboratory, Health Services Laboratory

Nov 27, 2014

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.90
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs66494441; hg19: chr2-241808463;