rs10813816

Variant names:

• chr9-32437251-T-C
• rs10813816
• NM_002197.3:c.2247+854T>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.2247+854T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,020 control chromosomes in the GnomAD database, including 9,320 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 0.35 (9320 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.349
• Publications: 14 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=-0.71).
• 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.2247+854T>C		intron_variant	Intron 18 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.2247+854T>C		intron_variant	Intron 19 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.2247+854T>C		intron_variant	Intron 19 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.2271+854T>C		intron_variant	Intron 18 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.2247+854T>C		intron_variant	Intron 18 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.2247+854T>C		intron_variant	Intron 19 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.2247+854T>C		intron_variant	Intron 19 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53005 AN: 151902 Hom.: 9308 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.366

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

GnomAD4 genome AF: 0.349 AC: 53050 AN: 152020 Hom.: 9320 Cov.: 32 AF XY: 0.348 AC XY: 25855 AN XY: 74292

African (AFR) AF: 0.331 AC: 13742 AN: 41456

American (AMR) AF: 0.361 AC: 5513 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3470

East Asian (EAS) AF: 0.511 AC: 2644 AN: 5172

South Asian (SAS) AF: 0.254 AC: 1226 AN: 4818

European-Finnish (FIN) AF: 0.324 AC: 3416 AN: 10558

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23968 AN: 67960

Other (OTH) AF: 0.373 AC: 787 AN: 2108

Alfa AF: 0.352 Hom.: 14778

Bravo AF: 0.354

Asia WGS AF: 0.384 AC: 1334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.35
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: rs10813816; hg19: chr9-32437249;