rs10970974

Variant names:

• chr9-32428068-A-C
• rs10970974
• NM_002197.3:c.1484+632A>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.1484+632A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 151,706 control chromosomes in the GnomAD database, including 2,526 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 0.16 (2526 hom., cov: 30)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1484+632A>C		intron_variant	Intron 12 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1484+632A>C		intron_variant	Intron 13 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.1484+632A>C		intron_variant	Intron 13 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.1508+632A>C		intron_variant	Intron 12 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.1484+632A>C		intron_variant	Intron 12 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1484+632A>C		intron_variant	Intron 13 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1484+632A>C		intron_variant	Intron 13 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23732 AN: 151590 Hom.: 2524 Cov.: 30

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.156 AC: 23729 AN: 151706 Hom.: 2526 Cov.: 30 AF XY: 0.159 AC XY: 11765 AN XY: 74132

African (AFR) AF: 0.0375 AC: 1553 AN: 41404

American (AMR) AF: 0.124 AC: 1885 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3466

East Asian (EAS) AF: 0.0382 AC: 197 AN: 5158

South Asian (SAS) AF: 0.293 AC: 1400 AN: 4784

European-Finnish (FIN) AF: 0.221 AC: 2308 AN: 10456

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.223 AC: 15133 AN: 67900

Other (OTH) AF: 0.155 AC: 325 AN: 2094

Alfa AF: 0.185 Hom.: 380

Bravo AF: 0.140

Asia WGS AF: 0.153 AC: 537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.83
PhyloP100		0.24
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: rs10970974; hg19: chr9-32428066;