chr2-240869070-A-C

Variant names:

• chr2-240869070-A-C
• rs57017537
• NM_000030.3:c.165+40A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000030.3(AGXT):​c.165+40A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 106,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00076 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGXT NM_000030.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -1.35
• Publications: 3 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000297735 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-240869070-A-C is Benign according to our data. Variant chr2-240869070-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 204026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.165+40A>C		intron	N/A	NP_000021.1	P21549

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.165+40A>C		intron	N/A	ENSP00000302620.3	P21549
	AGXT	ENST00000908235.1		c.165+40A>C		intron	N/A	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.165+40A>C		intron	N/A	ENSP00000578295.1

Frequencies

GnomAD3 genomes AF: 0.000385 AC: 41 AN: 106446 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000499

Gnomad OTH AF: 0.000703

GnomAD2 exomes AF: 0.00464 AC: 825 AN: 177854 AF XY: 0.00374

Gnomad AFR exome AF: 0.00972

Gnomad AMR exome AF: 0.000762

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.00104

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.00502

Gnomad OTH exome AF: 0.00404

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000764 AC: 1073 AN: 1404558 Hom.: 1 Cov.: 32 AF XY: 0.000797 AC XY: 558 AN XY: 700052

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

African (AFR) AF: 0.000793 AC: 26 AN: 32776

American (AMR) AF: 0.000249 AC: 11 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.000751 AC: 19 AN: 25316

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39482

South Asian (SAS) AF: 0.000520 AC: 44 AN: 84608

European-Finnish (FIN) AF: 0.00322 AC: 159 AN: 49354

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5644

European-Non Finnish (NFE) AF: 0.000727 AC: 774 AN: 1064696

Other (OTH) AF: 0.000444 AC: 26 AN: 58502

⚠️ 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 AF: 0.000385 AC: 41 AN: 106446 Hom.: 0 Cov.: 30 AF XY: 0.000440 AC XY: 23 AN XY: 52216

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

African (AFR) AF: 0.000383 AC: 12 AN: 31372

American (AMR) AF: 0.000170 AC: 2 AN: 11792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2366

East Asian (EAS) AF: 0.00 AC: 0 AN: 4456

South Asian (SAS) AF: 0.00103 AC: 4 AN: 3902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 198

European-Non Finnish (NFE) AF: 0.000499 AC: 22 AN: 44072

Other (OTH) AF: 0.000703 AC: 1 AN: 1422

⚠️ 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: 0.0760 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	Primary hyperoxaluria, type I (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.65
PhyloP100		-1.3
PromoterAI		0.011	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: rs57017537; hg19: chr2-241808487; COSMIC: COSV56755570; COSMIC: COSV56755570;