NM_000030.3:c.777-1G>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000030.3(AGXT):c.777-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000291 in 1,614,076 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

AGXT
NM_000030.3 splice_acceptor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.80

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-240875934-G-C is Pathogenic according to our data. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240875934-G-C is described in CliVar as Pathogenic. Clinvar id is 188774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3 link	c.777-1G>C		splice_acceptor_variant, intron_variant	Intron 7 of 10	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 link	c.777-1G>C		splice_acceptor_variant, intron_variant	Intron 7 of 10	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000476698.1 link	n.429-1G>C		splice_acceptor_variant, intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251268

AF XY:

0.0000147

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000396

AC:

AN:

1111994

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:5

Dec 27, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 18, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Primary hyperoxaluria

Pathogenic:1

Jun 03, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AGXT c.777-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251268 control chromosomes (gnomAD). The variant, c.777-1G>C, has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria Type 1 (Coulter-Mackie_2004, Coulter-Mackie_2005, Monico_2007, Williams_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication, Coulter-Mackie_2004, reports AGT activity of this variant from a patients liver biopsy was <10% of normal activity. One ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 7 of the AGXT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGXT are known to be pathogenic (PMID: 19479957). This variant is present in population databases (rs180177267, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with primary hyperoxaluria type 1 (PMID: 15110324, 15963748, 17460142, 25629080). ClinVar contains an entry for this variant (Variation ID: 188774). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.8

GERP RS

4.9

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.85

Position offset: 1

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over