rs10970972

Variant names:

• chr9-32424212-C-T
• rs10970972
• NM_002197.3:c.1072-337C>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.1072-337C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 151,954 control chromosomes in the GnomAD database, including 8,882 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 (8882 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 8 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 = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1072-337C>T		intron_variant	Intron 9 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1072-337C>T		intron_variant	Intron 10 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.1072-337C>T		intron_variant	Intron 10 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.1096-337C>T		intron_variant	Intron 9 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.1072-337C>T		intron_variant	Intron 9 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1072-337C>T		intron_variant	Intron 10 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1072-337C>T		intron_variant	Intron 10 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50489 AN: 151838 Hom.: 8869 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.0993

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.332 AC: 50524 AN: 151954 Hom.: 8882 Cov.: 32 AF XY: 0.331 AC XY: 24595 AN XY: 74254

African (AFR) AF: 0.277 AC: 11488 AN: 41424

American (AMR) AF: 0.332 AC: 5071 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1706 AN: 3468

East Asian (EAS) AF: 0.0998 AC: 516 AN: 5172

South Asian (SAS) AF: 0.451 AC: 2166 AN: 4806

European-Finnish (FIN) AF: 0.335 AC: 3537 AN: 10570

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24807 AN: 67934

Other (OTH) AF: 0.339 AC: 714 AN: 2108

Alfa AF: 0.362 Hom.: 17457

Bravo AF: 0.325

Asia WGS AF: 0.282 AC: 981 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	5.8
DANN	Benign	0.72
PhyloP100		0.15
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: rs10970972; hg19: chr9-32424210;