rs4879583

chr9-32412293-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002197.3(ACO1):c.404+3642C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,136 control chromosomes in the GnomAD database, including 1,653 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 0.14 (1653 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACO1	NM_002197.3	c.404+3642C>A		intron_variant		ENST00000309951.8
ACO1	NM_001278352.2	c.404+3642C>A		intron_variant
ACO1	NM_001362840.2	c.404+3642C>A		intron_variant
ACO1	XM_047423430.1	c.428+3642C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACO1	ENST00000309951.8	c.404+3642C>A		intron_variant		1	NM_002197.3	P1
ACO1	ENST00000379923.5	c.404+3642C>A		intron_variant		5		P1
ACO1	ENST00000541043.5	c.404+3642C>A		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20689 AN: 152018 Hom.: 1652 Cov.: 32

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.138

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

GnomAD4 genome AF: 0.136 AC: 20692 AN: 152136 Hom.: 1653 Cov.: 32 AF XY: 0.139 AC XY: 10321 AN XY: 74368

Gnomad4 AFR AF: 0.0666

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.135

Alfa AF: 0.133 Hom.: 369

Bravo AF: 0.130

Asia WGS AF: 0.230 AC: 803 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.035
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs4879583; hg19: chr9-32412291;