rs2026739

Variant names:

• chr9-32418239-G-T
• rs2026739
• NM_002197.3:c.474+42G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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=-0.84).
• 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 rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.474+42G>T		intron_variant	Intron 5 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.474+42G>T		intron_variant	Intron 6 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.474+42G>T		intron_variant	Intron 6 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.498+42G>T		intron_variant	Intron 5 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.474+42G>T		intron_variant	Intron 5 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.474+42G>T		intron_variant	Intron 6 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.474+42G>T		intron_variant	Intron 6 of 21	5		ENSP00000438733.2

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

GnomAD2 exomes AF: 0.690 AC: 172862 AN: 250590 AF XY: 0.697

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 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

African (AFR) AF: 0.593 AC: 19825 AN: 33456

American (AMR) AF: 0.644 AC: 28788 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.810 AC: 21171 AN: 26126

East Asian (EAS) AF: 0.601 AC: 23852 AN: 39686

South Asian (SAS) AF: 0.732 AC: 63103 AN: 86224

European-Finnish (FIN) AF: 0.630 AC: 33661 AN: 53404

Middle Eastern (MID) AF: 0.783 AC: 4514 AN: 5768

European-Non Finnish (NFE) AF: 0.714 AC: 793503 AN: 1110988

Other (OTH) AF: 0.704 AC: 42516 AN: 60354

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

African (AFR) AF: 0.599 AC: 24837 AN: 41444

American (AMR) AF: 0.671 AC: 10245 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2815 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3265 AN: 5164

South Asian (SAS) AF: 0.737 AC: 3554 AN: 4822

European-Finnish (FIN) AF: 0.637 AC: 6730 AN: 10560

Middle Eastern (MID) AF: 0.784 AC: 229 AN: 292

European-Non Finnish (NFE) AF: 0.715 AC: 48582 AN: 67966

Other (OTH) AF: 0.706 AC: 1488 AN: 2108

Alfa AF: 0.706 Hom.: 146777

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
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2026739; hg19: chr9-32418237; COSMIC: COSV59380245;