2-240869171-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000030.3(AGXT):c.167T>G(p.Ile56Ser) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I56N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGXT
NM_000030.3 missense, splice_region

Scores

Splicing: ADA: 0.4868

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.64

Publications

10 publications found

Variant links:

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: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

AGXT links:

ENSG00000297735 (HGNC:):

ENSG00000297735 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240869171-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204077.

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 alanine glyoxylate aminotransferase deficiency, primary hyperoxaluria type 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	NM_000030.3	MANE Select	c.167T>G	p.Ile56Ser	missense splice_region	Exon 2 of 11	NP_000021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGXT	ENST00000307503.4	TSL:1 MANE Select	c.167T>G	p.Ile56Ser	missense splice_region	Exon 2 of 11	ENSP00000302620.3
AGXT	ENST00000472436.1	TSL:2	n.187T>G		splice_region non_coding_transcript_exon	Exon 2 of 5
ENSG00000297735	ENST00000750632.1		n.237+1062A>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000175

AC:

AN:

114168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000147

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.37e-7

AC:

AN:

1356180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673260

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31398

American (AMR)

AF:

0.00

AC:

AN:

42280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22670

East Asian (EAS)

AF:

0.00

AC:

AN:

36900

South Asian (SAS)

AF:

0.00

AC:

AN:

82484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5164

European-Non Finnish (NFE)

AF:

9.63e-7

AC:

AN:

1038844

Other (OTH)

AF:

0.00

AC:

AN:

54022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000175

AC:

AN:

114168

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

55700

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33398

American (AMR)

AF:

0.00

AC:

AN:

12118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2570

East Asian (EAS)

AF:

0.00

AC:

AN:

4560

South Asian (SAS)

AF:

0.00

AC:

AN:

3996

European-Finnish (FIN)

AF:

0.000147

AC:

AN:

6782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

48398

Other (OTH)

AF:

0.00

AC:

AN:

1518

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.6

PhyloP100

5.6

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.85

Sift

Uncertain

0.023

Sift4G

Uncertain

0.036

Polyphen

0.99

Vest4

0.80

MutPred

0.67

Gain of disorder (P = 0.0034)

MVP

0.94

MPC

0.24

ClinPred

0.99

GERP RS

4.1

PromoterAI

-0.038

Neutral

(source)

Varity_R

0.79

gMVP

0.96

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.49

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over