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 Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV000239611: Mutation causes folding defect and reduces thermal stability on the background of either major or minor allele (PMID:32792227)." and additional evidence is available in ClinVar.

• 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:5 U:2
• Conservation: PhyloP100: 5.64
• Publications: 11 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000239611: Mutation causes folding defect and reduces thermal stability on the background of either major or minor allele (PMID:32792227).; SCV003928787: Experimental evidence demonstrated the variant affects protein function (Lage_2014, Dindo_2018, Dindo_2020).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 VariationId is 204077.

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.167T>A	p.Ile56Asn	missense splice_region	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.167T>A	p.Ile56Asn	missense splice_region	Exon 2 of 11	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.167T>A	p.Ile56Asn	missense splice_region	Exon 2 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.167T>A	p.Ile56Asn	missense splice_region	Exon 2 of 12	ENSP00000578295.1

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

African (AFR) AF: 0.00 AC: 0 AN: 31398

American (AMR) AF: 0.00 AC: 0 AN: 42280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22670

East Asian (EAS) AF: 0.00 AC: 0 AN: 36900

South Asian (SAS) AF: 0.000352 AC: 29 AN: 82484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1038844

Other (OTH) 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Primary hyperoxaluria, type I (5)
-	1	-	not provided (1)
1	-	-	Primary hyperoxaluria (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.6
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
PromoterAI		0.0094	Neutral
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

Other links and lift over

dbSNP: rs180177180; hg19: chr2-241808588;