rs7866419

Variant names:

• chr9-32387684-A-C
• rs7866419
• NM_002197.3:c.-23+2949A>C

Variant summary

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

The NM_002197.3(ACO1):​c.-23+2949A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 151,994 control chromosomes in the GnomAD database, including 20,293 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 0.51 (20293 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 7 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.-23+2949A>C		intron_variant	Intron 1 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.-23+1242A>C		intron_variant	Intron 2 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.-23+1246A>C		intron_variant	Intron 2 of 21		NP_001349769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.-23+2949A>C		intron_variant	Intron 1 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.-23+1246A>C		intron_variant	Intron 2 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.-23+1242A>C		intron_variant	Intron 2 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77269 AN: 151876 Hom.: 20263 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.509 AC: 77352 AN: 151994 Hom.: 20293 Cov.: 32 AF XY: 0.505 AC XY: 37525 AN XY: 74288

African (AFR) AF: 0.449 AC: 18593 AN: 41424

American (AMR) AF: 0.526 AC: 8035 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1283 AN: 3472

East Asian (EAS) AF: 0.225 AC: 1163 AN: 5174

South Asian (SAS) AF: 0.365 AC: 1759 AN: 4822

European-Finnish (FIN) AF: 0.542 AC: 5717 AN: 10550

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39146 AN: 67956

Other (OTH) AF: 0.488 AC: 1032 AN: 2114

Alfa AF: 0.548 Hom.: 9135

Bravo AF: 0.506

Asia WGS AF: 0.329 AC: 1144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		1.7
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: rs7866419; hg19: chr9-32387682;