2-200661607-A-G

Variant names:

• chr2-200661607-A-G
• rs55754655
• NM_001159.4:c.3404A>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.3404A>G​(p.Asn1135Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,606,880 control chromosomes in the GnomAD database, including 15,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.15 (2171 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13439 hom.)
• Consequence: AOX1 NM_001159.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• Publications: 31 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=0.0047774613).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AOX1	NM_001159.4	MANE Select	c.3404A>G	p.Asn1135Ser	missense	Exon 30 of 35	NP_001150.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AOX1	ENST00000374700.7	TSL:1 MANE Select	c.3404A>G	p.Asn1135Ser	missense	Exon 30 of 35	ENSP00000363832.2
	AOX1	ENST00000485106.5	TSL:1	n.2143A>G		non_coding_transcript_exon	Exon 17 of 22
	AOX1	ENST00000260930.10	TSL:5	c.62A>G	p.Asn21Ser	missense	Exon 2 of 7	ENSP00000260930.6

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23381 AN: 152094 Hom.: 2165 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.0876

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.109 AC: 27197 AN: 250104 AF XY: 0.105

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.0933

Gnomad EAS exome AF: 0.00288

Gnomad FIN exome AF: 0.0916

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.128 AC: 186705 AN: 1454668 Hom.: 13439 Cov.: 30 AF XY: 0.125 AC XY: 90339 AN XY: 723920

African (AFR) AF: 0.254 AC: 8400 AN: 33116

American (AMR) AF: 0.0747 AC: 3332 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 2455 AN: 26056

East Asian (EAS) AF: 0.00182 AC: 72 AN: 39656

South Asian (SAS) AF: 0.0449 AC: 3865 AN: 86098

European-Finnish (FIN) AF: 0.0970 AC: 5176 AN: 53374

Middle Eastern (MID) AF: 0.120 AC: 689 AN: 5732

European-Non Finnish (NFE) AF: 0.140 AC: 155218 AN: 1105938

Other (OTH) AF: 0.125 AC: 7498 AN: 60120

GnomAD4 genome AF: 0.154 AC: 23416 AN: 152212 Hom.: 2171 Cov.: 33 AF XY: 0.148 AC XY: 10981 AN XY: 74426

African (AFR) AF: 0.256 AC: 10635 AN: 41496

American (AMR) AF: 0.102 AC: 1560 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 331 AN: 3472

East Asian (EAS) AF: 0.00424 AC: 22 AN: 5186

South Asian (SAS) AF: 0.0375 AC: 181 AN: 4828

European-Finnish (FIN) AF: 0.0876 AC: 929 AN: 10610

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9375 AN: 68010

Other (OTH) AF: 0.145 AC: 306 AN: 2112

Alfa AF: 0.140 Hom.: 5997

Bravo AF: 0.161

TwinsUK AF: 0.145 AC: 539

ALSPAC AF: 0.141 AC: 544

ESP6500AA AF: 0.258 AC: 1137

ESP6500EA AF: 0.130 AC: 1116

ExAC AF: 0.115 AC: 13983

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.18
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		2.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.057
MPC		0.077
ClinPred		0.0041	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.19
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55754655; hg19: chr2-201526330; COSMIC: COSV107295414; COSMIC: COSV107295414;