rs114286107

chr5-35012953-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_031900.4(AGXT2):c.1188+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,551,610 control chromosomes in the GnomAD database, including 261 homozygotes. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 33)
  • Exomes 𝑓: 0.016 (241 hom.)
• Consequence: AGXT2 NM_031900.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.36

Genes affected

AGXT2 (HGNC:14412): (alanine--glyoxylate aminotransferase 2) The protein encoded by this gene is a class III pyridoxal-phosphate-dependent mitochondrial aminotransferase. It catalyzes the conversion of glyoxylate to glycine using L-alanine as the amino donor. It is an important regulator of methylarginines and is involved in the control of blood pressure in kidney. Polymorphisms in this gene affect methylarginine and beta-aminoisobutyrate metabolism, and are associated with carotid atherosclerosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-35012953-C-T is Benign according to our data. Variant chr5-35012953-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-35012953-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0123 (1875/152332) while in subpopulation NFE AF= 0.0164 (1119/68030). AF 95% confidence interval is 0.0156. There are 20 homozygotes in gnomad4. There are 999 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGXT2	NM_031900.4	c.1188+1G>A		splice_donor_variant		ENST00000231420.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGXT2	ENST00000231420.11	c.1188+1G>A		splice_donor_variant		1	NM_031900.4	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1879 AN: 152214 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0352

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0124 AC: 1933 AN: 156400 Hom.: 21 AF XY: 0.0123 AC XY: 1015 AN XY: 82252

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00751

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00671

Gnomad FIN exome AF: 0.0322

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0159 AC: 22251 AN: 1399278 Hom.: 241 Cov.: 31 AF XY: 0.0157 AC XY: 10862 AN XY: 690156

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.00717

Gnomad4 ASJ exome AF: 0.00802

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00659

Gnomad4 FIN exome AF: 0.0321

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0123 AC: 1875 AN: 152332 Hom.: 20 Cov.: 33 AF XY: 0.0134 AC XY: 999 AN XY: 74488

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.0352

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0148 Hom.: 37

Bravo AF: 0.00986

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00177 AC: 7

ESP6500EA AF: 0.0141 AC: 105

ExAC AF: 0.00596 AC: 287

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 112/11414=0.98%; Frequency in ESP (EUR): 105/7450=1.4% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114286107; hg19: chr5-35013058;