rs180177180

Variant names:

• chr2-240869171-T-A
• rs180177180
• NM_000030.3:c.167T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-240869171-T-A
• chr2-240869171-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PP2 PP3_Strong PP5

The NM_000030.3(AGXT):​c.167T>A​(p.Ile56Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000028 in 1,356,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: AGXT NM_000030.3 missense, splice_region
• Scores: Splicing: ADA: 0.4409
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 5.64

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000030.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 130 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: -0.26789 (below the threshold of 3.09). Trascript score misZ: -0.48778 (below the threshold of 3.09). GenCC associations: The gene is linked to primary hyperoxaluria type 1, alanine glyoxylate aminotransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 2-240869171-T-A is Pathogenic according to our data. Variant chr2-240869171-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204077.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.167T>A	p.Ile56Asn	missense_variant, splice_region_variant	Exon 2 of 11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.167T>A	p.Ile56Asn	missense_variant, splice_region_variant	Exon 2 of 11	1	NM_000030.3	ENSP00000302620.3
AGXT	ENST00000472436.1	n.187T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251234 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 38 AN: 1356182 Hom.: 0 Cov.: 34 AF XY: 0.0000297 AC XY: 20 AN XY: 673262

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31398

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 42280

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22670

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 36900

Gnomad4 SAS exome AF: 0.000352 AC: 29 AN: 82484

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 42420

Gnomad4 NFE exome AF: 0.00000193 AC: 2 AN: 1038844

Gnomad4 Remaining exome AF: 0.000130 AC: 7 AN: 54022

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary hyperoxaluria, type I Pathogenic:3 Uncertain:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mutation causes folding defect and reduces thermal stability on the background of either major or minor allele (PMID:32792227). ACMG:PS3 PM2 PP3 PP5 -

Oct 27, 2023

Thalassemia Center, San Luigi University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG:PS3 PM2 PP3 PP5 -

Primary hyperoxaluria Pathogenic:1

Apr 05, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGXT c.167T>A (p.Ile56Asn) results in a non-conservative amino acid change located in the Aminotransferase class V domain (IPR000192) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251834 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (5.6e-05 vs 0.0024), allowing no conclusion about variant significance. c.167T>A has been reported in the literature in individuals affected with Primary Hyperoxaluria Type 1 (M'dimegh_2016, Krishnamurthy_2017). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Lage_2014, Dindo_2018, Dindo_2020). 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 likely pathogenic. -

not provided Uncertain:1

Nov 18, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the apparent homozygous state in an individual with nephrocalcinosis, but this individual was also homozygous for another variant in the AGXT gene (Krishnamurthy et al., 2017); Reported in several publications, but detailed clinical information was not provided and it was not clear if these individuals harbored a second AGXT variant on the other allele (Williams et al., 2009; M'dimegh et al., 2017; Chatterjee et al., 2022); Published functional studies suggest a damaging effect: reduced expression and stability and increased aggregation propensity, particularly if found in combination with the P11L minor allele (Lage et al., 2014; Dindo et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27935012, 29663716, 24718375, 29110180, 19479957, 35695965, 33457257, Chatterjee2022[paper], 28904440, 32792227) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.92		Gain of disorder (P = 0.0174);
MVP		0.96
MPC		0.30
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.96
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.44
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.060		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: rs180177180; hg19: chr2-241808588;