rs1028932

Variant names:

• chr9-32391786-C-G
• rs1028932
• NM_002197.3:c.-23+7051C>G

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+7051C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,096 control chromosomes in the GnomAD database, including 14,801 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 0.43 (14801 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.602
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.-23+7051C>G		intron_variant	Intron 1 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.-23+5344C>G		intron_variant	Intron 2 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.-23+5348C>G		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+7051C>G		intron_variant	Intron 1 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.-23+5348C>G		intron_variant	Intron 2 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.-23+5344C>G		intron_variant	Intron 2 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65853 AN: 151978 Hom.: 14779 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.433 AC: 65918 AN: 152096 Hom.: 14801 Cov.: 33 AF XY: 0.428 AC XY: 31795 AN XY: 74344

African (AFR) AF: 0.357 AC: 14814 AN: 41466

American (AMR) AF: 0.475 AC: 7249 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1209 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1155 AN: 5184

South Asian (SAS) AF: 0.342 AC: 1647 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4261 AN: 10558

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34108 AN: 68010

Other (OTH) AF: 0.427 AC: 903 AN: 2114

Alfa AF: 0.469 Hom.: 2108

Bravo AF: 0.435

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		0.60
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: rs1028932; hg19: chr9-32391784;