chr17-42844773-C-A

Variant names:

• chr17-42844773-C-A
• rs145927458
• NM_009590.4:c.147C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_009590.4(AOC2):​c.147C>A​(p.His49Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: AOC2 NM_009590.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.485

Genes affected

AOC2 (HGNC:549): (amine oxidase copper containing 2) Copper amine oxidases catalyze the oxidative conversion of amines to aldehydes and ammonia in the presence of copper and quinone cofactor. This gene shows high sequence similarity to copper amine oxidases from various species ranging from bacteria to mammals. The protein contains several conserved motifs including the active site of amine oxidases and the histidine residues that likely bind copper. It may be a critical modulator of signal transmission in retina, possibly by degrading the biogenic amines dopamine, histamine, and putrescine. This gene may be a candidate gene for hereditary ocular diseases. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007014543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AOC2	NM_009590.4	c.147C>A	p.His49Gln	missense_variant	Exon 1 of 4	ENST00000253799.8	NP_033720.2
AOC2	NM_001158.5	c.147C>A	p.His49Gln	missense_variant	Exon 1 of 4		NP_001149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AOC2	ENST00000253799.8	c.147C>A	p.His49Gln	missense_variant	Exon 1 of 4	1	NM_009590.4	ENSP00000253799.2
AOC2	ENST00000452774.2	c.147C>A	p.His49Gln	missense_variant	Exon 1 of 4	1		ENSP00000406134.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00121 AC: 305 AN: 251432 Hom.: 0 AF XY: 0.00120 AC XY: 163 AN XY: 135888

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00139 AC: 2029 AN: 1461878 Hom.: 1 Cov.: 33 AF XY: 0.00135 AC XY: 980 AN XY: 727244

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74506

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00199 Hom.: 1

Bravo AF: 0.00113

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.147C>A (p.H49Q) alteration is located in exon 1 (coding exon 1) of the AOC2 gene. This alteration results from a C to A substitution at nucleotide position 147, causing the histidine (H) at amino acid position 49 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.0
DANN	Benign	0.93
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.055
Sift	Benign	0.036	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.015	B;B
Vest4		0.21
MutPred		0.25		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.25
MPC		0.026
ClinPred		0.015	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs145927458; hg19: chr17-40996790;