Genetic Variant AOX1:p.Val280Ile (chr2-200605559-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001159.4(AOX1):c.838G>A(p.Val280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,545,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

AOX1
NM_001159.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.131

Publications

2 publications found

Variant links:

Genes affected

AOX1 (HGNC:553): (aldehyde oxidase 1) Aldehyde oxidase produces hydrogen peroxide and, under certain conditions, can catalyze the formation of superoxide. Aldehyde oxidase is a candidate gene for amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

AOX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00684458).

BP6

Variant 2-200605559-G-A is Benign according to our data. Variant chr2-200605559-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3876422.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159.4. 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
	AOX1	NM_001159.4	MANE Select	c.838G>A	p.Val280Ile	missense	Exon 10 of 35	NP_001150.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AOX1	ENST00000374700.7	TSL:1 MANE Select	c.838G>A	p.Val280Ile	missense	Exon 10 of 35	ENSP00000363832.2	Q06278
AOX1	ENST00000854909.1		c.838G>A	p.Val280Ile	missense	Exon 10 of 36	ENSP00000524968.1
AOX1	ENST00000854911.1		c.838G>A	p.Val280Ile	missense	Exon 10 of 35	ENSP00000524970.1

Frequencies

GnomAD3 genomes

AF:

0.0000870

AC:

AN:

149420

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000633

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000739

Gnomad OTH

AF:

0.000490

GnomAD2 exomes

AF:

0.000157

AC:

AN:

216438

AF XY:

0.000238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000395

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000881

AC:

123

AN:

1395740

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

693086

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30626

American (AMR)

AF:

0.0000264

AC:

AN:

37924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24560

East Asian (EAS)

AF:

0.00

AC:

AN:

36894

South Asian (SAS)

AF:

0.000808

AC:

AN:

73056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.0000500

AC:

AN:

1079014

Other (OTH)

AF:

0.000140

AC:

AN:

57210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000869

AC:

AN:

149532

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

72704

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40706

American (AMR)

AF:

0.000134

AC:

AN:

14962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.000634

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000739

AC:

AN:

67676

Other (OTH)

AF:

0.000485

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000602

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000198

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.9

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.074

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.59

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.17

PhyloP100

-0.13

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.18

REVEL

Benign

0.0050

Sift

Benign

0.66

Sift4G

Benign

0.79

Polyphen

0.0020

Vest4

0.084

MVP

0.099

MPC

0.082

ClinPred

0.0042

GERP RS

-1.5

Varity_R

0.082

gMVP

0.22

Mutation Taster

=97/3

polymorphism

(source)

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

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