rs17288067

Variant names:

• chr9-32409048-G-A
• rs17288067
• NM_002197.3:c.404+397G>A

Variant summary

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

The NM_002197.3(ACO1):​c.404+397G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,122 control chromosomes in the GnomAD database, including 2,059 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (2059 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 5 publications found

Genes affected

ACO1 (HGNC:117): (aconitase 1) The protein encoded by this gene is a bifunctional, cytosolic protein that functions as an essential enzyme in the TCA cycle and interacts with mRNA to control the levels of iron inside cells. When cellular iron levels are high, this protein binds to a 4Fe-4S cluster and functions as an aconitase. Aconitases are iron-sulfur proteins that function to catalyze the conversion of citrate to isocitrate. When cellular iron levels are low, the protein binds to iron-responsive elements (IREs), which are stem-loop structures found in the 5' UTR of ferritin mRNA, and in the 3' UTR of transferrin receptor mRNA. When the protein binds to IRE, it results in repression of translation of ferritin mRNA, and inhibition of degradation of the otherwise rapidly degraded transferrin receptor mRNA. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alternative splicing results in multiple transcript variants [provided by RefSeq, Jan 2014]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.404+397G>A		intron_variant	Intron 4 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.404+397G>A		intron_variant	Intron 5 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.404+397G>A		intron_variant	Intron 5 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.428+397G>A		intron_variant	Intron 4 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.404+397G>A		intron_variant	Intron 4 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.404+397G>A		intron_variant	Intron 5 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.404+397G>A		intron_variant	Intron 5 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21854 AN: 152004 Hom.: 2058 Cov.: 33

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0326

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.163

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.144 AC: 21846 AN: 152122 Hom.: 2059 Cov.: 33 AF XY: 0.144 AC XY: 10670 AN XY: 74346

African (AFR) AF: 0.0359 AC: 1492 AN: 41546

American (AMR) AF: 0.189 AC: 2893 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 689 AN: 3472

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5178

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4810

European-Finnish (FIN) AF: 0.153 AC: 1617 AN: 10564

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.189 AC: 12870 AN: 67950

Other (OTH) AF: 0.161 AC: 341 AN: 2112

Alfa AF: 0.194 Hom.: 1784

Bravo AF: 0.138

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		0.0050
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17288067; hg19: chr9-32409046;