9-32422404-A-T

Variant names:

• chr9-32422404-A-T
• rs10813813
• NM_002197.3:c.971-915A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002197.3(ACO1):​c.971-915A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 152,008 control chromosomes in the GnomAD database, including 9,057 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 0.34 (9057 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.166
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.971-915A>T		intron_variant	Intron 8 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.971-915A>T		intron_variant	Intron 9 of 21		NP_001265281.1
ACO1	NM_001362840.2	c.971-915A>T		intron_variant	Intron 9 of 21		NP_001349769.1
ACO1	XM_047423430.1	c.995-915A>T		intron_variant	Intron 8 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.971-915A>T		intron_variant	Intron 8 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.971-915A>T		intron_variant	Intron 9 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.971-915A>T		intron_variant	Intron 9 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51243 AN: 151890 Hom.: 9053 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.337 AC: 51245 AN: 152008 Hom.: 9057 Cov.: 32 AF XY: 0.335 AC XY: 24899 AN XY: 74304

African (AFR) AF: 0.293 AC: 12163 AN: 41474

American (AMR) AF: 0.333 AC: 5090 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1715 AN: 3468

East Asian (EAS) AF: 0.100 AC: 518 AN: 5176

South Asian (SAS) AF: 0.450 AC: 2166 AN: 4814

European-Finnish (FIN) AF: 0.335 AC: 3529 AN: 10542

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24810 AN: 67944

Other (OTH) AF: 0.348 AC: 734 AN: 2112

Alfa AF: 0.219 Hom.: 487

Bravo AF: 0.331

Asia WGS AF: 0.279 AC: 972 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.37
DANN	Benign	0.43
PhyloP100		-0.17
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: rs10813813; hg19: chr9-32422402; COSMIC: COSV59378407;