chr9-32431933-A-G

Variant names:

• chr9-32431933-A-G
• rs10970975
• NM_002197.3:c.1851+90A>G

Variant summary

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

The NM_002197.3(ACO1):​c.1851+90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,443,732 control chromosomes in the GnomAD database, including 86,664 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 0.34 (9135 hom., cov: 31)
  • Exomes 𝑓: 0.34 (77529 hom.)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.690

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1851+90A>G		intron_variant	Intron 15 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1851+90A>G		intron_variant	Intron 16 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.1851+90A>G		intron_variant	Intron 16 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.1875+90A>G		intron_variant	Intron 15 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.1851+90A>G		intron_variant	Intron 15 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1851+90A>G		intron_variant	Intron 16 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1851+90A>G		intron_variant	Intron 16 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52302 AN: 151856 Hom.: 9113 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.344 AC: 444462 AN: 1291758 Hom.: 77529 AF XY: 0.342 AC XY: 219823 AN XY: 643080

Gnomad4 AFR exome AF: 0.317

Gnomad4 AMR exome AF: 0.346

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.335

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.345

GnomAD4 genome AF: 0.345 AC: 52369 AN: 151974 Hom.: 9135 Cov.: 31 AF XY: 0.343 AC XY: 25476 AN XY: 74272

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.363

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.352

Gnomad4 OTH AF: 0.379

Alfa AF: 0.226 Hom.: 522

Bravo AF: 0.350

Asia WGS AF: 0.393 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs10970975; hg19: chr9-32431931; COSMIC: COSV59381561;