9-32403292-C-T

Variant names:

• chr9-32403292-C-T
• rs10970961
• NM_002197.3:c.-22-2193C>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.-22-2193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,064 control chromosomes in the GnomAD database, including 6,955 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 0.28 (6955 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	NM_002197.3	MANE Select	c.-22-2193C>T		intron	N/A	NP_002188.1
	ACO1	NM_001278352.2		c.-22-2193C>T		intron	N/A	NP_001265281.1
	ACO1	NM_001362840.2		c.-22-2193C>T		intron	N/A	NP_001349769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.-22-2193C>T		intron	N/A	ENSP00000309477.5
	ACO1	ENST00000379923.5	TSL:5	c.-22-2193C>T		intron	N/A	ENSP00000369255.1
	ACO1	ENST00000541043.5	TSL:5	c.-22-2193C>T		intron	N/A	ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42994 AN: 151944 Hom.: 6948 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.435

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.283 AC: 43012 AN: 152064 Hom.: 6955 Cov.: 32 AF XY: 0.279 AC XY: 20779 AN XY: 74354

African (AFR) AF: 0.134 AC: 5553 AN: 41476

American (AMR) AF: 0.359 AC: 5490 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3470

East Asian (EAS) AF: 0.222 AC: 1146 AN: 5164

South Asian (SAS) AF: 0.298 AC: 1436 AN: 4824

European-Finnish (FIN) AF: 0.229 AC: 2424 AN: 10578

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24835 AN: 67964

Other (OTH) AF: 0.304 AC: 641 AN: 2112

Alfa AF: 0.342 Hom.: 38925

Bravo AF: 0.285

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.6
DANN	Benign	0.58
PhyloP100		0.29
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: rs10970961; hg19: chr9-32403290;