rs17288914

Positions:

• chr9-32452629-T-C

Variant summary

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

The NM_002197.3(ACO1):​c.*2518T>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 0.175 in 151,850 control chromosomes in the GnomAD database, including 2,618 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 0.17 (2618 hom., cov: 31)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: ACO1 NM_002197.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.370

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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.*2518T>C		3_prime_UTR_variant	21/21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.*2518T>C		3_prime_UTR_variant	22/22		NP_001265281.1
ACO1	NM_001362840.2	c.*2518T>C		3_prime_UTR_variant	22/22		NP_001349769.1
ACO1	XM_047423430.1	c.*2518T>C		3_prime_UTR_variant	21/21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.*2518T>C		3_prime_UTR_variant	21/21	1	NM_002197.3	ENSP00000309477.5

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26539 AN: 151718 Hom.: 2617 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0622

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.143 AC: 2 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 2 AN XY: 8

Gnomad4 NFE exome AF: 0.143

GnomAD4 genome AF: 0.175 AC: 26557 AN: 151836 Hom.: 2618 Cov.: 31 AF XY: 0.177 AC XY: 13111 AN XY: 74206

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.212

Gnomad4 OTH AF: 0.157

Alfa AF: 0.201 Hom.: 3188

Bravo AF: 0.162

Asia WGS AF: 0.183 AC: 638 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.48
DANN	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17288914; hg19: chr9-32452627;