chr2-240868867-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_SupportingPM2PP5_Very_Strong

The NM_000030.3(AGXT):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000683 in 1,610,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

AGXT
NM_000030.3 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.12

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 111 CDS bases. Genomic position: 240868976. Lost 0.094 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-240868867-T-C is Pathogenic according to our data. Variant chr2-240868867-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204065.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.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENST00000307503.4	NP_000021.1	P21549

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11	1	NM_000030.3	ENSP00000302620.3		P21549
AGXT	ENST00000472436.1 link	n.22T>C		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000457

AC:

AN:

240536

Hom.:

AF XY:

0.0000534

AC XY:

AN XY:

131184

show subpopulations

Gnomad AFR exome

AF:

0.0000660

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000499

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000935

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458064

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary hyperoxaluria, type I

Pathogenic:6

Aug 26, 2024

Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Conserved/phastCons:Conserved/gnomAD_exome_EastAsian:0.0005/ExAC_EastAsian:0.0003/dbSNP:rs138584408 -

May 18, 2017

Counsyl

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

- -

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary hyperoxaluria

Pathogenic:1

Jul 31, 2024

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.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Next inframe start codon is located at p.M38. Variants upstream of this position have been classified Pathogenic in ClinVar (CV IDs: 188957,204069, 204072). Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 240536 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AGXT causing Primary Hyperoxaluria Type 1 (4.6e-05 vs 0.0024), allowing no conclusion about variant significance. c.2T>C has been reported in the literature in individuals affected with Primary Hyperoxaluria (examples:Li_2014, Yuen_2004, Lin_2021, Xin_2023). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 37139236, 24934730, 33721035,15365967). ClinVar contains an entry for this variant (Variation ID: 204065). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the AGXT mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs138584408, gnomAD 0.05%). Disruption of the initiator codon has been observed in individuals with primary hyperoxaluria type 1 (PMID: 15365967, 24934730, 29456205). ClinVar contains an entry for this variant (Variation ID: 204065). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects AGXT function (PMID: 17495019). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

0.79

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.96

Vest4

0.94

MVP

0.97

ClinPred

0.53

GERP RS

4.3

Varity_R

0.64

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over