Genetic Variant ACO1:c.2556+165T>C (chr9-32449246-T-C) – 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.2556+165T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 151,970 control chromosomes in the GnomAD database, including 23,938 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 0.56 ( 23938 hom., cov: 31)

Consequence

ACO1
NM_002197.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.07

Publications

19 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=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACO1	NM_002197.3	MANE Select	c.2556+165T>C	intron	N/A	NP_002188.1	P21399
ACO1	NM_001278352.2		c.2556+165T>C	intron	N/A	NP_001265281.1	P21399
ACO1	NM_001362840.2		c.2556+165T>C	intron	N/A	NP_001349769.1	P21399

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACO1	ENST00000309951.8	TSL:1 MANE Select	c.2556+165T>C	intron	N/A	ENSP00000309477.5	P21399
ACO1	ENST00000963208.1		c.2586+165T>C	intron	N/A	ENSP00000633267.1
ACO1	ENST00000379923.5	TSL:5	c.2556+165T>C	intron	N/A	ENSP00000369255.1	P21399

Frequencies

GnomAD3 genomes

AF:

0.561

AC:

85165

AN:

151848

Hom.:

23915

Cov.:

show subpopulations

Gnomad AFR

AF:

0.548

Gnomad AMI

AF:

0.532

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.578

Gnomad EAS

AF:

0.587

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.529

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.550

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

GnomAD4 genome

AF:

0.561

AC:

85227

AN:

151970

Hom.:

23938

Cov.:

AF XY:

0.560

AC XY:

41571

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.547

AC:

22668

AN:

41412

American (AMR)

AF:

0.501

AC:

7644

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.578

AC:

2006

AN:

3472

East Asian (EAS)

AF:

0.587

AC:

3027

AN:

5158

South Asian (SAS)

AF:

0.581

AC:

2798

AN:

4818

European-Finnish (FIN)

AF:

0.545

AC:

5767

AN:

10574

Middle Eastern (MID)

AF:

0.541

AC:

158

AN:

292

European-Non Finnish (NFE)

AF:

0.581

AC:

39501

AN:

67948

Other (OTH)

AF:

0.555

AC:

1175

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1900

3801

5701

7602

9502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.572

Hom.:

57025

Bravo

AF:

0.557

Asia WGS

AF:

0.569

AC:

1980

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.3

(source)

DANN

Benign

0.42

PhyloP100

-1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over