9-32425678-T-G

Variant summary

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

The NM_002197.3(ACO1):c.1189-160T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 152,036 control chromosomes in the GnomAD database, including 12,745 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 0.40 (12745 hom., cov: 33)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94

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=-0.58).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACO1	NM_002197.3	c.1189-160T>G		intron_variant		ENST00000309951.8
ACO1	NM_001278352.2	c.1189-160T>G		intron_variant
ACO1	NM_001362840.2	c.1189-160T>G		intron_variant
ACO1	XM_047423430.1	c.1213-160T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACO1	ENST00000309951.8	c.1189-160T>G		intron_variant		1	NM_002197.3	P1
ACO1	ENST00000379923.5	c.1189-160T>G		intron_variant		5		P1
ACO1	ENST00000541043.5	c.1189-160T>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60791 AN: 151918 Hom.: 12715 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.402

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

GnomAD4 genome AF: 0.400 AC: 60869 AN: 152036 Hom.: 12745 Cov.: 33 AF XY: 0.399 AC XY: 29650 AN XY: 74330

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.372

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.407

Alfa AF: 0.340 Hom.: 4156

Bravo AF: 0.410

Asia WGS AF: 0.422 AC: 1464 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	11
Dann	Benign	0.88

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: rs3780474; hg19: chr9-32425676;