9-32416483-C-T

Variant names:

• chr9-32416483-C-T
• rs13292540
• NM_002197.3:c.405-1645C>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.405-1645C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,004 control chromosomes in the GnomAD database, including 7,043 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 0.28 (7043 hom., cov: 31)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.468
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.405-1645C>T		intron_variant	Intron 4 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.405-1645C>T		intron_variant	Intron 5 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.405-1645C>T		intron_variant	Intron 5 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.429-1645C>T		intron_variant	Intron 4 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.405-1645C>T		intron_variant	Intron 4 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.405-1645C>T		intron_variant	Intron 5 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.405-1645C>T		intron_variant	Intron 5 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42219 AN: 151886 Hom.: 7034 Cov.: 31

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.305

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

GnomAD4 genome AF: 0.278 AC: 42237 AN: 152004 Hom.: 7043 Cov.: 31 AF XY: 0.275 AC XY: 20413 AN XY: 74310

African (AFR) AF: 0.0949 AC: 3935 AN: 41480

American (AMR) AF: 0.304 AC: 4641 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3460

East Asian (EAS) AF: 0.259 AC: 1338 AN: 5172

South Asian (SAS) AF: 0.266 AC: 1282 AN: 4812

European-Finnish (FIN) AF: 0.285 AC: 3015 AN: 10568

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25890 AN: 67942

Other (OTH) AF: 0.310 AC: 652 AN: 2100

Alfa AF: 0.331 Hom.: 7125

Bravo AF: 0.271

Asia WGS AF: 0.273 AC: 948 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.51
PhyloP100		-0.47
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: rs13292540; hg19: chr9-32416481;