chr2-240869171-T-G

Position:

• chr2-240869171-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3_Moderate

The NM_000030.3(AGXT):​c.167T>G​(p.Ile56Ser) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I56N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGXT NM_000030.3 missense, splice_region
• Scores: Splicing: ADA: 0.4868
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 17) in uniprot entity AGT1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000030.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240869171-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204077.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT	NM_000030.3	c.167T>G	p.Ile56Ser	missense_variant, splice_region_variant	2/11	ENST00000307503.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT	ENST00000307503.4	c.167T>G	p.Ile56Ser	missense_variant, splice_region_variant	2/11	1	NM_000030.3	P1
AGXT	ENST00000472436.1	n.187T>G		splice_region_variant, non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 114168 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000147

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.37e-7 AC: 1 AN: 1356180 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 673260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.63e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000175 AC: 2 AN: 114168 Hom.: 0 Cov.: 31 AF XY: 0.0000180 AC XY: 1 AN XY: 55700

Gnomad4 AFR AF: 0.0000299

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000147

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.036	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.67		Gain of disorder (P = 0.0034);
MVP		0.94
MPC		0.24
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.79
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.49
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs180177180; hg19: chr2-241808588;