Genetic Variant AGXT:p.Met1? (chr2-240868867-T-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000030.3(AGXT):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000754 in 1,458,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

AGXT
NM_000030.3 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.12

Publications

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

AGXT links:

ENSG00000297735 (HGNC:):

ENSG00000297735 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 24 pathogenic variants. Next in-frame start position is after 38 codons. Genomic position: 240868977. Lost 0.095 part of the original CDS.

PS1

Another start lost variant in NM_000030.3 (AGXT) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

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.2T>A	p.Met1?	start_lost	Exon 1 of 11	NP_000021.1	P21549

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGXT	ENST00000307503.4	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 11	ENSP00000302620.3	P21549
AGXT	ENST00000908235.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000578294.1
AGXT	ENST00000908236.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458064

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111022

Other (OTH)

AF:

0.0000166

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.70

PhyloP100

4.1

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MutPred

0.98

Gain of MoRF binding (P = 0.0093)

MVP

0.97

ClinPred

0.98

GERP RS

4.3

PromoterAI

0.0031

Neutral

(source)

Varity_R

0.81

gMVP

0.91

Mutation Taster

=10/190

disease causing

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over