rs33958047

Variant names:

• chr2-240874036-G-A
• rs33958047
• NM_000030.3:c.654G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000030.3(AGXT):​c.654G>A​(p.Ser218Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,613,208 control chromosomes in the GnomAD database, including 9,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1383 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8611 hom.)
• Consequence: AGXT NM_000030.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: -5.20
• Publications: 16 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-240874036-G-A is Benign according to our data. Variant chr2-240874036-G-A is described in ClinVar as Benign. ClinVar VariationId is 198034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

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.654G>A	p.Ser218Ser	synonymous	Exon 6 of 11	NP_000021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGXT	ENST00000307503.4	TSL:1 MANE Select	c.654G>A	p.Ser218Ser	synonymous	Exon 6 of 11	ENSP00000302620.3
	AGXT	ENST00000908235.1		c.654G>A	p.Ser218Ser	synonymous	Exon 6 of 12	ENSP00000578294.1
	AGXT	ENST00000908236.1		c.654G>A	p.Ser218Ser	synonymous	Exon 6 of 12	ENSP00000578295.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19225 AN: 152044 Hom.: 1382 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.105 AC: 26405 AN: 251006 AF XY: 0.106

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0514

Gnomad ASJ exome AF: 0.0930

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.0887

Gnomad NFE exome AF: 0.0987

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.107 AC: 155817 AN: 1461046 Hom.: 8611 Cov.: 33 AF XY: 0.107 AC XY: 77810 AN XY: 726828

African (AFR) AF: 0.202 AC: 6753 AN: 33466

American (AMR) AF: 0.0537 AC: 2402 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 2484 AN: 26136

East Asian (EAS) AF: 0.157 AC: 6233 AN: 39694

South Asian (SAS) AF: 0.121 AC: 10469 AN: 86254

European-Finnish (FIN) AF: 0.0884 AC: 4676 AN: 52898

Middle Eastern (MID) AF: 0.117 AC: 674 AN: 5768

European-Non Finnish (NFE) AF: 0.103 AC: 115031 AN: 1111732

Other (OTH) AF: 0.118 AC: 7095 AN: 60378

GnomAD4 genome AF: 0.126 AC: 19240 AN: 152162 Hom.: 1383 Cov.: 33 AF XY: 0.127 AC XY: 9452 AN XY: 74386

African (AFR) AF: 0.198 AC: 8234 AN: 41496

American (AMR) AF: 0.0725 AC: 1109 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 322 AN: 3468

East Asian (EAS) AF: 0.160 AC: 827 AN: 5162

South Asian (SAS) AF: 0.130 AC: 626 AN: 4804

European-Finnish (FIN) AF: 0.0879 AC: 933 AN: 10612

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6901 AN: 68000

Other (OTH) AF: 0.103 AC: 219 AN: 2116

Alfa AF: 0.114 Hom.: 657

Bravo AF: 0.128

Asia WGS AF: 0.165 AC: 572 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Primary hyperoxaluria, type I (5)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.068
DANN	Benign	0.48
PhyloP100		-5.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33958047; hg19: chr2-241813453; COSMIC: COSV56753400; COSMIC: COSV56753400;