chr9-32450189-T-C

Variant names:

• chr9-32450189-T-C
• rs12985
• NM_002197.3:c.*78T>C

Variant summary

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

The NM_002197.3(ACO1):​c.*78T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,149,134 control chromosomes in the GnomAD database, including 83,903 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 0.39 (11793 hom., cov: 31)
  • Exomes 𝑓: 0.38 (72110 hom.)
• Consequence: ACO1 NM_002197.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.420
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002197.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	NM_002197.3	MANE Select	c.*78T>C		3_prime_UTR	Exon 21 of 21	NP_002188.1
	ACO1	NM_001278352.2		c.*78T>C		3_prime_UTR	Exon 22 of 22	NP_001265281.1
	ACO1	NM_001362840.2		c.*78T>C		3_prime_UTR	Exon 22 of 22	NP_001349769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.*78T>C		3_prime_UTR	Exon 21 of 21	ENSP00000309477.5
	ACO1	ENST00000379923.5	TSL:5	c.*78T>C		3_prime_UTR	Exon 22 of 22	ENSP00000369255.1
	ACO1	ENST00000541043.5	TSL:5	c.*78T>C		3_prime_UTR	Exon 22 of 22	ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59495 AN: 151764 Hom.: 11773 Cov.: 31

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.411

GnomAD2 exomes AF: 0.384 AC: 91771 AN: 238836 AF XY: 0.376

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.551

Gnomad FIN exome AF: 0.376

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.378 AC: 376574 AN: 997252 Hom.: 72110 Cov.: 14 AF XY: 0.372 AC XY: 191843 AN XY: 516172

African (AFR) AF: 0.408 AC: 9906 AN: 24264

American (AMR) AF: 0.361 AC: 15618 AN: 43222

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 10225 AN: 23218

East Asian (EAS) AF: 0.470 AC: 17660 AN: 37538

South Asian (SAS) AF: 0.236 AC: 18054 AN: 76516

European-Finnish (FIN) AF: 0.379 AC: 19805 AN: 52256

Middle Eastern (MID) AF: 0.337 AC: 1107 AN: 3286

European-Non Finnish (NFE) AF: 0.385 AC: 266706 AN: 692142

Other (OTH) AF: 0.390 AC: 17493 AN: 44810

GnomAD4 genome AF: 0.392 AC: 59559 AN: 151882 Hom.: 11793 Cov.: 31 AF XY: 0.390 AC XY: 28966 AN XY: 74234

African (AFR) AF: 0.411 AC: 17010 AN: 41412

American (AMR) AF: 0.382 AC: 5833 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1478 AN: 3472

East Asian (EAS) AF: 0.524 AC: 2671 AN: 5102

South Asian (SAS) AF: 0.246 AC: 1181 AN: 4806

European-Finnish (FIN) AF: 0.363 AC: 3829 AN: 10562

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.386 AC: 26219 AN: 67942

Other (OTH) AF: 0.418 AC: 878 AN: 2102

Alfa AF: 0.390 Hom.: 15671

Bravo AF: 0.400

Asia WGS AF: 0.399 AC: 1388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.43
DANN	Benign	0.23
PhyloP100		-0.42
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: rs12985; hg19: chr9-32450187;