rs10970986

Positions:

• chr9-32453280-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.*3169T>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 0.223 in 150,158 control chromosomes in the GnomAD database, including 4,483 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 0.22 (4483 hom., cov: 28)
  • Failed GnomAD Quality Control
• Consequence: ACO1 NM_002197.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.489

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.*3169T>C		3_prime_UTR_variant	21/21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.*3169T>C		3_prime_UTR_variant	22/22		NP_001265281.1
ACO1	NM_001362840.2	c.*3169T>C		3_prime_UTR_variant	22/22		NP_001349769.1
ACO1	XM_047423430.1	c.*3169T>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.*3169T>C		3_prime_UTR_variant	21/21	1	NM_002197.3	ENSP00000309477	P1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33438 AN: 150042 Hom.: 4472 Cov.: 28

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.263

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.223 AC: 33448 AN: 150158 Hom.: 4483 Cov.: 28 AF XY: 0.220 AC XY: 16126 AN XY: 73180

Gnomad4 AFR AF: 0.0597

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.273

Alfa AF: 0.286 Hom.: 8785

Bravo AF: 0.218

Asia WGS AF: 0.260 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.6
DANN	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10970986; hg19: chr9-32453278;