rs7022554

Positions:

• chr9-32436016-A-G

Variant summary

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

The NM_002197.3(ACO1):​c.2100-234A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 669,714 control chromosomes in the GnomAD database, including 105,270 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 0.56 (23979 hom., cov: 32)
  • Exomes 𝑓: 0.56 (81291 hom.)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292

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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.2100-234A>G		intron_variant		ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.2100-234A>G		intron_variant			NP_001265281.1
ACO1	NM_001362840.2	c.2100-234A>G		intron_variant			NP_001349769.1
ACO1	XM_047423430.1	c.2124-234A>G		intron_variant			XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.2100-234A>G		intron_variant		1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.2100-234A>G		intron_variant		5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.2100-234A>G		intron_variant		5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85212 AN: 151910 Hom.: 23935 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.551

GnomAD3 exomes AF: 0.545 AC: 74495 AN: 136642 Hom.: 20577 AF XY: 0.551 AC XY: 40735 AN XY: 73898

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.565

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.532

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.557 AC: 288561 AN: 517686 Hom.: 81291 Cov.: 4 AF XY: 0.560 AC XY: 157703 AN XY: 281560

Gnomad4 AFR exome AF: 0.576

Gnomad4 AMR exome AF: 0.453

Gnomad4 ASJ exome AF: 0.565

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.573

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.572

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.561 AC: 85305 AN: 152028 Hom.: 23979 Cov.: 32 AF XY: 0.560 AC XY: 41594 AN XY: 74278

Gnomad4 AFR AF: 0.576

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.550

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.570

Gnomad4 OTH AF: 0.556

Alfa AF: 0.560 Hom.: 15535

Bravo AF: 0.558

Asia WGS AF: 0.570 AC: 1985 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	2.1
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7022554; hg19: chr9-32436014; COSMIC: COSV59381132;