2-240869114-C-T

Variant names:

• chr2-240869114-C-T
• rs114401766
• NM_000030.3:c.166-56C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000030.3(AGXT):​c.166-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.266
• Publications: 2 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: G2P, Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGXT	NM_000030.3	c.166-56C>T		intron_variant	Intron 1 of 10	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.166-56C>T		intron_variant	Intron 1 of 10	1	NM_000030.3	ENSP00000302620.3

Frequencies

GnomAD3 genomes AF: 0.000883 AC: 94 AN: 106498 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000413

Gnomad AMI AF: 0.00195

Gnomad AMR AF: 0.000931

Gnomad ASJ AF: 0.000848

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000767

Gnomad FIN AF: 0.00205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.000707

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00542 AC: 5704 AN: 1052898 Hom.: 0 Cov.: 31 AF XY: 0.00486 AC XY: 2569 AN XY: 528282

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

African (AFR) AF: 0.00203 AC: 55 AN: 27108

American (AMR) AF: 0.000408 AC: 16 AN: 39190

Ashkenazi Jewish (ASJ) AF: 0.00201 AC: 40 AN: 19882

East Asian (EAS) AF: 0.0000856 AC: 3 AN: 35052

South Asian (SAS) AF: 0.000645 AC: 49 AN: 75946

European-Finnish (FIN) AF: 0.00124 AC: 46 AN: 37076

Middle Eastern (MID) AF: 0.00228 AC: 10 AN: 4382

European-Non Finnish (NFE) AF: 0.00692 AC: 5326 AN: 769218

Other (OTH) AF: 0.00353 AC: 159 AN: 45044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000882 AC: 94 AN: 106582 Hom.: 0 Cov.: 30 AF XY: 0.00107 AC XY: 56 AN XY: 52436

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

African (AFR) AF: 0.000412 AC: 13 AN: 31528

American (AMR) AF: 0.000929 AC: 11 AN: 11836

Ashkenazi Jewish (ASJ) AF: 0.000848 AC: 2 AN: 2358

East Asian (EAS) AF: 0.00 AC: 0 AN: 4458

South Asian (SAS) AF: 0.000769 AC: 3 AN: 3902

European-Finnish (FIN) AF: 0.00205 AC: 13 AN: 6344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.00114 AC: 50 AN: 44024

Other (OTH) AF: 0.000695 AC: 1 AN: 1438

⚠️ 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.

Alfa AF: 0.110 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary hyperoxaluria, type I Uncertain:1

Nov 27, 2014

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		0.27
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114401766; hg19: chr2-241808531; COSMIC: COSV56753026; COSMIC: COSV56753026;