rs7042042

Positions:

• chr9-32451146-A-G

Variant summary

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

The ENST00000309951.8(ACO1):​c.*1035A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,888 control chromosomes in the GnomAD database, including 29,205 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 0.62 (29202 hom., cov: 31)
  • Exomes 𝑓: 0.88 (3 hom.)
• Consequence: ACO1 ENST00000309951.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.10

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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.*1035A>G		3_prime_UTR_variant	21/21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.*1035A>G		3_prime_UTR_variant	22/22		NP_001265281.1
ACO1	NM_001362840.2	c.*1035A>G		3_prime_UTR_variant	22/22		NP_001349769.1
ACO1	XM_047423430.1	c.*1035A>G		3_prime_UTR_variant	21/21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.*1035A>G		3_prime_UTR_variant	21/21	1	NM_002197.3	ENSP00000309477	P1

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93780 AN: 151764 Hom.: 29160 Cov.: 31

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.593

GnomAD4 exome AF: 0.875 AC: 7 AN: 8 Hom.: 3 Cov.: 0 AF XY: 0.875 AC XY: 7 AN XY: 8

Gnomad4 SAS exome AF: 0.500

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.618 AC: 93871 AN: 151880 Hom.: 29202 Cov.: 31 AF XY: 0.617 AC XY: 45809 AN XY: 74216

Gnomad4 AFR AF: 0.546

Gnomad4 AMR AF: 0.606

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.583

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.665

Gnomad4 OTH AF: 0.599

Alfa AF: 0.655 Hom.: 65807

Bravo AF: 0.612

Asia WGS AF: 0.608 AC: 2115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.040
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7042042; hg19: chr9-32451144; COSMIC: COSV59384398; COSMIC: COSV59384398;