9-32425272-G-A

Variant names:

• chr9-32425272-G-A
• rs13293491
• NM_002197.3:c.1189-566G>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.1189-566G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 152,090 control chromosomes in the GnomAD database, including 8,061 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 0.32 (8061 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 6 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002197.3. 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
	ACO1	NM_002197.3	MANE Select	c.1189-566G>A		intron	N/A	NP_002188.1
	ACO1	NM_001278352.2		c.1189-566G>A		intron	N/A	NP_001265281.1
	ACO1	NM_001362840.2		c.1189-566G>A		intron	N/A	NP_001349769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.1189-566G>A		intron	N/A	ENSP00000309477.5
	ACO1	ENST00000379923.5	TSL:5	c.1189-566G>A		intron	N/A	ENSP00000369255.1
	ACO1	ENST00000541043.5	TSL:5	c.1189-566G>A		intron	N/A	ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48137 AN: 151972 Hom.: 8055 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.317 AC: 48162 AN: 152090 Hom.: 8061 Cov.: 33 AF XY: 0.317 AC XY: 23561 AN XY: 74368

African (AFR) AF: 0.237 AC: 9826 AN: 41468

American (AMR) AF: 0.320 AC: 4886 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1081 AN: 3470

East Asian (EAS) AF: 0.531 AC: 2747 AN: 5174

South Asian (SAS) AF: 0.284 AC: 1370 AN: 4820

European-Finnish (FIN) AF: 0.302 AC: 3188 AN: 10558

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23859 AN: 68012

Other (OTH) AF: 0.351 AC: 741 AN: 2112

Alfa AF: 0.336 Hom.: 17203

Bravo AF: 0.315

Asia WGS AF: 0.402 AC: 1395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.42
PhyloP100		0.089
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: rs13293491; hg19: chr9-32425270;