2-200669666-A-G

Variant names:

• chr2-200669666-A-G
• rs3731722
• NM_001159.4:c.3890A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001159.4(AOX1):​c.3890A>G​(p.His1297Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0683 in 1,613,922 control chromosomes in the GnomAD database, including 4,273 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.069 (434 hom., cov: 31)
  • Exomes 𝑓: 0.068 (3839 hom.)
• Consequence: AOX1 NM_001159.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.57
• Publications: 28 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016839206).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AOX1	NM_001159.4	c.3890A>G	p.His1297Arg	missense_variant	Exon 34 of 35	ENST00000374700.7	NP_001150.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AOX1	ENST00000374700.7	c.3890A>G	p.His1297Arg	missense_variant	Exon 34 of 35	1	NM_001159.4	ENSP00000363832.2

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10384 AN: 151998 Hom.: 424 Cov.: 31

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.0797

Gnomad SAS AF: 0.0904

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0594

GnomAD2 exomes AF: 0.0795 AC: 19981 AN: 251412 AF XY: 0.0786

Gnomad AFR exome AF: 0.0409

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0357

Gnomad EAS exome AF: 0.0798

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0655

GnomAD4 exome AF: 0.0682 AC: 99750 AN: 1461806 Hom.: 3839 Cov.: 32 AF XY: 0.0690 AC XY: 50146 AN XY: 727204

African (AFR) AF: 0.0401 AC: 1342 AN: 33478

American (AMR) AF: 0.132 AC: 5910 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 897 AN: 26136

East Asian (EAS) AF: 0.0716 AC: 2843 AN: 39692

South Asian (SAS) AF: 0.0905 AC: 7810 AN: 86252

European-Finnish (FIN) AF: 0.108 AC: 5761 AN: 53414

Middle Eastern (MID) AF: 0.0302 AC: 174 AN: 5768

European-Non Finnish (NFE) AF: 0.0640 AC: 71122 AN: 1111962

Other (OTH) AF: 0.0644 AC: 3891 AN: 60394

GnomAD4 genome AF: 0.0685 AC: 10425 AN: 152116 Hom.: 434 Cov.: 31 AF XY: 0.0707 AC XY: 5257 AN XY: 74372

African (AFR) AF: 0.0449 AC: 1862 AN: 41514

American (AMR) AF: 0.114 AC: 1735 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3468

East Asian (EAS) AF: 0.0801 AC: 414 AN: 5168

South Asian (SAS) AF: 0.0909 AC: 437 AN: 4806

European-Finnish (FIN) AF: 0.109 AC: 1155 AN: 10580

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0669 AC: 4550 AN: 68000

Other (OTH) AF: 0.0579 AC: 122 AN: 2108

Alfa AF: 0.0641 Hom.: 924

Bravo AF: 0.0657

TwinsUK AF: 0.0674 AC: 250

ALSPAC AF: 0.0636 AC: 245

ESP6500AA AF: 0.0474 AC: 209

ESP6500EA AF: 0.0590 AC: 507

ExAC AF: 0.0755 AC: 9170

Asia WGS AF: 0.0790 AC: 273 AN: 3478

EpiCase AF: 0.0594

EpiControl AF: 0.0574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0050
DANN	Benign	0.22
DEOGEN2	Benign	0.091	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.13	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.085	N;.;.
PhyloP100		-3.6
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.71	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.011
MPC		0.12
ClinPred		0.0072	T
GERP RS		-11
Varity_R		0.16
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3731722; hg19: chr2-201534389; COSMIC: COSV53495624;