dbSNP rs114286107: AGXT2:c.1188+1G>A (chr5-35012953-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_031900.4(AGXT2):c.1188+1G>A variant causes a splice donor, intron 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. 3/3 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, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.36

Publications

8 publications found

Variant links:

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]

AGXT2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 402346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031900.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AGXT2	NM_031900.4	MANE Select	c.1188+1G>A	splice_donor intron	N/A	NP_114106.1	Q9BYV1-1
AGXT2	NM_001438583.1		c.1185+1G>A	splice_donor intron	N/A	NP_001425512.1
AGXT2	NM_001438584.1		c.993+1G>A	splice_donor intron	N/A	NP_001425513.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AGXT2	ENST00000231420.11	TSL:1 MANE Select	c.1188+1G>A	splice_donor intron	N/A	ENSP00000231420.6	Q9BYV1-1
AGXT2	ENST00000510428.1	TSL:1	c.964-2804G>A	intron	N/A	ENSP00000422799.1	Q9BYV1-2
AGXT2	ENST00000853198.1		c.1269+1G>A	splice_donor intron	N/A	ENSP00000523257.1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1879

AN:

152214

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0124

AC:

1933

AN:

156400

AF XY:

0.0123

show subpopulations

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 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.:

AF XY:

0.0157

AC XY:

10862

AN XY:

690156

show subpopulations

African (AFR)

AF:

0.00326

AC:

103

AN:

31596

American (AMR)

AF:

0.00717

AC:

256

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00802

AC:

202

AN:

25182

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35736

South Asian (SAS)

AF:

0.00659

AC:

522

AN:

79232

European-Finnish (FIN)

AF:

0.0321

AC:

1580

AN:

49274

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0173

AC:

18660

AN:

1078858

Other (OTH)

AF:

0.0146

AC:

848

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

1134

2269

3403

4538

5672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0123

AC:

1875

AN:

152332

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

999

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41584

American (AMR)

AF:

0.0100

AC:

153

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00581

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0352

AC:

374

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0164

AC:

1119

AN:

68030

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0150

Hom.:

Bravo

AF:

0.00986

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.00177

AC:

ESP6500EA

AF:

0.0141

AC:

105

ExAC

AF:

0.00596

AC:

287

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.4

GERP RS

5.4

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over