chr9-32398236-G-T

Variant names:

• chr9-32398236-G-T
• rs7033149
• NM_002197.3:c.-22-7249G>T

Variant summary

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

The NM_002197.3(ACO1):​c.-22-7249G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,178 control chromosomes in the GnomAD database, including 50,032 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 0.81 (50032 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882
• Publications: 8 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.-22-7249G>T		intron_variant	Intron 1 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.-22-7249G>T		intron_variant	Intron 2 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.-22-7249G>T		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.-22-7249G>T		intron_variant	Intron 1 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.-22-7249G>T		intron_variant	Intron 2 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.-22-7249G>T		intron_variant	Intron 2 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.809 AC: 122953 AN: 152060 Hom.: 50000 Cov.: 33

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.854

Gnomad OTH AF: 0.836

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

GnomAD4 genome AF: 0.809 AC: 123041 AN: 152178 Hom.: 50032 Cov.: 33 AF XY: 0.805 AC XY: 59852 AN XY: 74390

African (AFR) AF: 0.724 AC: 30049 AN: 41498

American (AMR) AF: 0.845 AC: 12931 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 3224 AN: 3468

East Asian (EAS) AF: 0.723 AC: 3743 AN: 5176

South Asian (SAS) AF: 0.851 AC: 4104 AN: 4822

European-Finnish (FIN) AF: 0.762 AC: 8069 AN: 10590

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.854 AC: 58059 AN: 68000

Other (OTH) AF: 0.835 AC: 1767 AN: 2116

Alfa AF: 0.843 Hom.: 144642

Bravo AF: 0.810

Asia WGS AF: 0.799 AC: 2780 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.22
PhyloP100		-0.88
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: rs7033149; hg19: chr9-32398234; COSMIC: COSV59378243;