dbSNP rs10970961: ACO1:c.-22-2193C>T (chr9-32403292-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002197.3(ACO1):c.-22-2193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,064 control chromosomes in the GnomAD database, including 6,955 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 0.28 ( 6955 hom., cov: 32)

Consequence

ACO1
NM_002197.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.292

Publications

6 publications found

Variant links:

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]

ACO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ACO1	NM_002197.3 link	c.-22-2193C>T	intron_variant	Intron 1 of 20	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2 link	c.-22-2193C>T	intron_variant	Intron 2 of 21		NP_001265281.1
ACO1	NM_001362840.2 link	c.-22-2193C>T	intron_variant	Intron 2 of 21		NP_001349769.1
ACO1	XM_047423430.1 link	c.3-2193C>T	intron_variant	Intron 1 of 20		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ACO1	ENST00000309951.8 link	c.-22-2193C>T	intron_variant	Intron 1 of 20	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5 link	c.-22-2193C>T	intron_variant	Intron 2 of 21	5		ENSP00000369255.1
ACO1	ENST00000541043.5 link	c.-22-2193C>T	intron_variant	Intron 2 of 21	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

42994

AN:

151944

Hom.:

6948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.360

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.298

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

GnomAD4 genome

AF:

0.283

AC:

43012

AN:

152064

Hom.:

6955

Cov.:

AF XY:

0.279

AC XY:

20779

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.134

AC:

5553

AN:

41476

American (AMR)

AF:

0.359

AC:

5490

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

1020

AN:

3470

East Asian (EAS)

AF:

0.222

AC:

1146

AN:

5164

South Asian (SAS)

AF:

0.298

AC:

1436

AN:

4824

European-Finnish (FIN)

AF:

0.229

AC:

2424

AN:

10578

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24835

AN:

67964

Other (OTH)

AF:

0.304

AC:

641

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1498

2995

4493

5990

7488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.342

Hom.:

38925

Bravo

AF:

0.285

Asia WGS

AF:

0.274

AC:

952

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.6

(source)

DANN

Benign

0.58

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over