rs180177176

chr2-240869156-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000030.3(AGXT):c.166-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,439,122 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 30)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: AGXT NM_000030.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -0.0600

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=-0.87).
• BP6: Variant 2-240869156-C-T is Benign according to our data. Variant chr2-240869156-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 204029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00458 (497/108398) while in subpopulation NFE AF= 0.00869 (388/44660). AF 95% confidence interval is 0.00797. There are 2 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.166-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.166-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.186-14C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 498 AN: 108308 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00126

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000505

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00871

Gnomad OTH AF: 0.00209

GnomAD3 exomes AF: 0.00347 AC: 868 AN: 250318 Hom.: 6 AF XY: 0.00338 AC XY: 458 AN XY: 135404

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00432 AC: 5749 AN: 1330724 Hom.: 24 Cov.: 34 AF XY: 0.00428 AC XY: 2830 AN XY: 660696

Gnomad4 AFR exome AF: 0.000615

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.000896

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.000362

Gnomad4 FIN exome AF: 0.00551

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00458 AC: 497 AN: 108398 Hom.: 2 Cov.: 30 AF XY: 0.00473 AC XY: 252 AN XY: 53250

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00126

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000505

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.00869

Gnomad4 OTH AF: 0.00206

Alfa AF: 0.00336 Hom.: 1

Bravo AF: 0.00282

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2020	Variant summary: AGXT c.166-14C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0036 in 274786 control chromosomes, predominantly at a frequency of 0.0059 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 phenotype (0.0024), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.166-14C>T has been reported in the literature as a polymorphic variant (Williams_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.8
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177176; hg19: chr2-241808573;