9-32417623-T-G

Variant names:

• chr9-32417623-T-G
• rs10435797
• NM_002197.3:c.405-505T>G

Variant summary

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

The NM_002197.3(ACO1):​c.405-505T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 152,058 control chromosomes in the GnomAD database, including 8,299 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 0.32 (8299 hom., cov: 32)
• Consequence: ACO1 NM_002197.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.394
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002197.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	NM_002197.3	MANE Select	c.405-505T>G		intron	N/A	NP_002188.1	P21399
	ACO1	NM_001278352.2		c.405-505T>G		intron	N/A	NP_001265281.1	P21399
	ACO1	NM_001362840.2		c.405-505T>G		intron	N/A	NP_001349769.1	P21399

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.405-505T>G		intron	N/A	ENSP00000309477.5	P21399
	ACO1	ENST00000963208.1		c.405-505T>G		intron	N/A	ENSP00000633267.1
	ACO1	ENST00000379923.5	TSL:5	c.405-505T>G		intron	N/A	ENSP00000369255.1	P21399

Frequencies

GnomAD3 genomes AF: 0.322 AC: 48991 AN: 151940 Hom.: 8283 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.322 AC: 49037 AN: 152058 Hom.: 8299 Cov.: 32 AF XY: 0.322 AC XY: 23965 AN XY: 74334

African (AFR) AF: 0.251 AC: 10388 AN: 41460

American (AMR) AF: 0.332 AC: 5082 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1102 AN: 3472

East Asian (EAS) AF: 0.527 AC: 2723 AN: 5170

South Asian (SAS) AF: 0.288 AC: 1387 AN: 4816

European-Finnish (FIN) AF: 0.301 AC: 3182 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23961 AN: 67946

Other (OTH) AF: 0.351 AC: 743 AN: 2116

Alfa AF: 0.335 Hom.: 2150

Bravo AF: 0.322

Asia WGS AF: 0.404 AC: 1402 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.53
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10435797; hg19: chr9-32417621;