NM_002197.3:c.1263A>G

Variant names:

• chr9-32425912-A-G
• rs3780473
• NM_002197.3:c.1263A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002197.3(ACO1):​c.1263A>G​(p.Glu421Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,612,936 control chromosomes in the GnomAD database, including 100,381 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 0.33 (8843 hom., cov: 32)
  • Exomes 𝑓: 0.35 (91538 hom.)
• Consequence: ACO1 NM_002197.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 24 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-0.082 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 11 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 12 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 12 of 22		NP_001349769.1
ACO1	XM_047423430.1	c.1287A>G	p.Glu429Glu	synonymous_variant	Exon 11 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 11 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 12 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1263A>G	p.Glu421Glu	synonymous_variant	Exon 12 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50525 AN: 151940 Hom.: 8828 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.353

GnomAD2 exomes AF: 0.346 AC: 86780 AN: 250774 AF XY: 0.344

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.547

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.351 AC: 513221 AN: 1460878 Hom.: 91538 Cov.: 34 AF XY: 0.350 AC XY: 254345 AN XY: 726762

African (AFR) AF: 0.265 AC: 8857 AN: 33452

American (AMR) AF: 0.338 AC: 15081 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8441 AN: 26120

East Asian (EAS) AF: 0.510 AC: 20249 AN: 39676

South Asian (SAS) AF: 0.291 AC: 25117 AN: 86198

European-Finnish (FIN) AF: 0.301 AC: 16095 AN: 53386

Middle Eastern (MID) AF: 0.276 AC: 1592 AN: 5768

European-Non Finnish (NFE) AF: 0.357 AC: 397184 AN: 1111248

Other (OTH) AF: 0.341 AC: 20605 AN: 60366

GnomAD4 genome AF: 0.333 AC: 50574 AN: 152058 Hom.: 8843 Cov.: 32 AF XY: 0.333 AC XY: 24736 AN XY: 74352

African (AFR) AF: 0.273 AC: 11323 AN: 41460

American (AMR) AF: 0.334 AC: 5107 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1120 AN: 3464

East Asian (EAS) AF: 0.540 AC: 2794 AN: 5170

South Asian (SAS) AF: 0.294 AC: 1415 AN: 4818

European-Finnish (FIN) AF: 0.309 AC: 3265 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24310 AN: 67976

Other (OTH) AF: 0.358 AC: 757 AN: 2112

Alfa AF: 0.347 Hom.: 18935

Bravo AF: 0.332

Asia WGS AF: 0.409 AC: 1421 AN: 3478

EpiCase AF: 0.356

EpiControl AF: 0.353

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.3
DANN	Benign	0.48
PhyloP100		-0.082
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: rs3780473; hg19: chr9-32425910; COSMIC: COSV59380370;