rs41304757

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002197.3(ACO1):c.367G>A(p.Val123Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,614,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V123L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 3 hom. )

Consequence

ACO1
NM_002197.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.23

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02454874).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACO1	NM_002197.3	MANE Select	c.367G>A	p.Val123Ile	missense	Exon 4 of 21	NP_002188.1	P21399
ACO1	NM_001278352.2		c.367G>A	p.Val123Ile	missense	Exon 5 of 22	NP_001265281.1	P21399
ACO1	NM_001362840.2		c.367G>A	p.Val123Ile	missense	Exon 5 of 22	NP_001349769.1	P21399

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACO1	ENST00000309951.8	TSL:1 MANE Select	c.367G>A	p.Val123Ile	missense	Exon 4 of 21	ENSP00000309477.5	P21399
ACO1	ENST00000963208.1		c.367G>A	p.Val123Ile	missense	Exon 4 of 21	ENSP00000633267.1
ACO1	ENST00000379923.5	TSL:5	c.367G>A	p.Val123Ile	missense	Exon 5 of 22	ENSP00000369255.1	P21399

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00135

AC:

340

AN:

251414

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00233

AC:

3404

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1664

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000783

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000742

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00283

AC:

3147

AN:

1111978

Other (OTH)

AF:

0.00205

AC:

124

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

174

349

523

698

872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00136

AC:

207

AN:

152318

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41556

American (AMR)

AF:

0.00144

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00226

AC:

154

AN:

68030

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00191

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00126

AC:

153

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0072

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

4.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.88

REVEL

Benign

0.15

Sift

Benign

0.11

Sift4G

Benign

0.13

Polyphen

0.0030

Vest4

0.33

MVP

0.37

MPC

0.19

ClinPred

0.032

GERP RS

5.7

Varity_R

0.25

gMVP

0.50

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over