9-32431933-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002197.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	NM_002197.3	MANE Select	c.1851+90A>G		intron	N/A	NP_002188.1	P21399
	ACO1	NM_001278352.2		c.1851+90A>G		intron	N/A	NP_001265281.1	P21399
	ACO1	NM_001362840.2		c.1851+90A>G		intron	N/A	NP_001349769.1	P21399

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.1851+90A>G		intron	N/A	ENSP00000309477.5	P21399
	ACO1	ENST00000963208.1		c.1881+90A>G		intron	N/A	ENSP00000633267.1
	ACO1	ENST00000379923.5	TSL:5	c.1851+90A>G		intron	N/A	ENSP00000369255.1	P21399

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

African (AFR) AF: 0.317 AC: 9006 AN: 28370

American (AMR) AF: 0.346 AC: 10645 AN: 30760

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 8074 AN: 21602

East Asian (EAS) AF: 0.463 AC: 17464 AN: 37750

South Asian (SAS) AF: 0.253 AC: 18716 AN: 73908

European-Finnish (FIN) AF: 0.335 AC: 15669 AN: 46818

Middle Eastern (MID) AF: 0.319 AC: 1525 AN: 4780

European-Non Finnish (NFE) AF: 0.347 AC: 344762 AN: 993830

Other (OTH) AF: 0.345 AC: 18601 AN: 53940

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

African (AFR) AF: 0.319 AC: 13222 AN: 41430

American (AMR) AF: 0.353 AC: 5393 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3468

East Asian (EAS) AF: 0.516 AC: 2657 AN: 5148

South Asian (SAS) AF: 0.254 AC: 1224 AN: 4818

European-Finnish (FIN) AF: 0.324 AC: 3425 AN: 10556

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23921 AN: 67952

Other (OTH) AF: 0.379 AC: 801 AN: 2114

Alfa AF: 0.234 Hom.: 566

Bravo AF: 0.350

Asia WGS AF: 0.393 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.77
DANN	Benign	0.69
PhyloP100		-0.69
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: rs10970975; hg19: chr9-32431931; COSMIC: COSV59381561;