rs7874815

Variant names:

• chr9-32417246-C-T
• rs7874815
• NM_002197.3:c.405-882C>T

Variant summary

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

The NM_002197.3(ACO1):​c.405-882C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 152,054 control chromosomes in the GnomAD database, including 35,030 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 0.68 (35030 hom., cov: 31)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.657

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=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.405-882C>T		intron_variant	Intron 4 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.405-882C>T		intron_variant	Intron 5 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.405-882C>T		intron_variant	Intron 5 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.429-882C>T		intron_variant	Intron 4 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.405-882C>T		intron_variant	Intron 4 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.405-882C>T		intron_variant	Intron 5 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.405-882C>T		intron_variant	Intron 5 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102876 AN: 151936 Hom.: 35007 Cov.: 31

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.707

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

GnomAD4 genome AF: 0.677 AC: 102943 AN: 152054 Hom.: 35030 Cov.: 31 AF XY: 0.675 AC XY: 50180 AN XY: 74332

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.817

Gnomad4 EAS AF: 0.634

Gnomad4 SAS AF: 0.759

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.709

Alfa AF: 0.709 Hom.: 19873

Bravo AF: 0.672

Asia WGS AF: 0.691 AC: 2401 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	0.17
DANN	Benign	0.29

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: rs7874815; hg19: chr9-32417244; COSMIC: COSV59378384;