rs4495514

Positions:

• chr9-32405182-C-T

Variant summary

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

The NM_002197.3(ACO1):​c.-22-303C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 152,260 control chromosomes in the GnomAD database, including 167 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 0.026 (167 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286

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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.-22-303C>T		intron_variant		ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.-22-303C>T		intron_variant			NP_001265281.1
ACO1	NM_001362840.2	c.-22-303C>T		intron_variant			NP_001349769.1
ACO1	XM_047423430.1	c.3-303C>T		intron_variant			XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.-22-303C>T		intron_variant		1	NM_002197.3	ENSP00000309477	P1
ACO1	ENST00000379923.5	c.-22-303C>T		intron_variant		5		ENSP00000369255	P1
ACO1	ENST00000541043.5	c.-22-303C>T		intron_variant		5		ENSP00000438733	P1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3942 AN: 152142 Hom.: 166 Cov.: 33

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0153

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

GnomAD4 genome AF: 0.0259 AC: 3946 AN: 152260 Hom.: 167 Cov.: 33 AF XY: 0.0248 AC XY: 1845 AN XY: 74442

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0219 Hom.: 6

Bravo AF: 0.0306

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.63

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: rs4495514; hg19: chr9-32405180;