9-32436016-A-G

Variant names:

• chr9-32436016-A-G
• rs7022554
• NM_002197.3:c.2100-234A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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 (SAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.2100-234A>G		intron_variant	Intron 17 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.2100-234A>G		intron_variant	Intron 18 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.2100-234A>G		intron_variant	Intron 18 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.2124-234A>G		intron_variant	Intron 17 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.2100-234A>G		intron_variant	Intron 17 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.2100-234A>G		intron_variant	Intron 18 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.2100-234A>G		intron_variant	Intron 18 of 21	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

GnomAD2 exomes AF: 0.545 AC: 74495 AN: 136642 AF XY: 0.551

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 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

African (AFR) AF: 0.576 AC: 8701 AN: 15112

American (AMR) AF: 0.453 AC: 15182 AN: 33534

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 10713 AN: 18958

East Asian (EAS) AF: 0.499 AC: 14460 AN: 28974

South Asian (SAS) AF: 0.573 AC: 35297 AN: 61612

European-Finnish (FIN) AF: 0.536 AC: 15886 AN: 29638

Middle Eastern (MID) AF: 0.562 AC: 2170 AN: 3860

European-Non Finnish (NFE) AF: 0.572 AC: 170226 AN: 297560

Other (OTH) AF: 0.560 AC: 15926 AN: 28438

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

African (AFR) AF: 0.576 AC: 23890 AN: 41448

American (AMR) AF: 0.499 AC: 7625 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1907 AN: 3470

East Asian (EAS) AF: 0.552 AC: 2852 AN: 5168

South Asian (SAS) AF: 0.589 AC: 2836 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5602 AN: 10546

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38769 AN: 67984

Other (OTH) AF: 0.556 AC: 1176 AN: 2114

Alfa AF: 0.561 Hom.: 19044

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
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7022554; hg19: chr9-32436014; COSMIC: COSV59381132;