rs2026739

Positions:

• chr9-32418239-G-T

Variant summary

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

The NM_002197.3(ACO1):​c.474+42G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,612,724 control chromosomes in the GnomAD database, including 399,857 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 0.67 (34775 hom., cov: 32)
  • Exomes 𝑓: 0.71 (365082 hom.)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144

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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACO1	NM_002197.3	c.474+42G>T		intron_variant		ENST00000309951.8
ACO1	NM_001278352.2	c.474+42G>T		intron_variant
ACO1	NM_001362840.2	c.474+42G>T		intron_variant
ACO1	XM_047423430.1	c.498+42G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACO1	ENST00000309951.8	c.474+42G>T		intron_variant		1	NM_002197.3	P1
ACO1	ENST00000379923.5	c.474+42G>T		intron_variant		5		P1
ACO1	ENST00000541043.5	c.474+42G>T		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102439 AN: 151896 Hom.: 34754 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.787

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.705

GnomAD3 exomes AF: 0.690 AC: 172862 AN: 250590 Hom.: 60003 AF XY: 0.697 AC XY: 94508 AN XY: 135626

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.807

Gnomad EAS exome AF: 0.629

Gnomad SAS exome AF: 0.730

Gnomad FIN exome AF: 0.631

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.706 AC: 1030933 AN: 1460710 Hom.: 365082 Cov.: 35 AF XY: 0.708 AC XY: 514520 AN XY: 726744

Gnomad4 AFR exome AF: 0.593

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.601

Gnomad4 SAS exome AF: 0.732

Gnomad4 FIN exome AF: 0.630

Gnomad4 NFE exome AF: 0.714

Gnomad4 OTH exome AF: 0.704

GnomAD4 genome AF: 0.674 AC: 102503 AN: 152014 Hom.: 34775 Cov.: 32 AF XY: 0.672 AC XY: 49956 AN XY: 74284

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.671

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.737

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.706

Alfa AF: 0.715 Hom.: 68262

Bravo AF: 0.669

Asia WGS AF: 0.685 AC: 2379 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2026739; hg19: chr9-32418237; COSMIC: COSV59380245;