rs10970976

Variant names:

• chr9-32433528-T-C
• rs10970976
• NM_002197.3:c.1852-200T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002197.3(ACO1):​c.1852-200T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 152,020 control chromosomes in the GnomAD database, including 8,023 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 0.32 (8023 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 10 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1852-200T>C		intron_variant	Intron 15 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1852-200T>C		intron_variant	Intron 16 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.1852-200T>C		intron_variant	Intron 16 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.1876-200T>C		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.1852-200T>C		intron_variant	Intron 15 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1852-200T>C		intron_variant	Intron 16 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1852-200T>C		intron_variant	Intron 16 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48936 AN: 151902 Hom.: 8003 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.322 AC: 48994 AN: 152020 Hom.: 8023 Cov.: 32 AF XY: 0.320 AC XY: 23789 AN XY: 74306

African (AFR) AF: 0.307 AC: 12715 AN: 41460

American (AMR) AF: 0.334 AC: 5101 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3470

East Asian (EAS) AF: 0.511 AC: 2640 AN: 5168

South Asian (SAS) AF: 0.250 AC: 1207 AN: 4824

European-Finnish (FIN) AF: 0.271 AC: 2863 AN: 10572

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22088 AN: 67948

Other (OTH) AF: 0.352 AC: 743 AN: 2108

Alfa AF: 0.329 Hom.: 13131

Bravo AF: 0.330

Asia WGS AF: 0.385 AC: 1340 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.70
DANN	Benign	0.71
PhyloP100		-1.8
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: rs10970976; hg19: chr9-32433526;