dbSNP rs7032871: ACO1:c.971-627T>A (chr9-32422692-T-A) – 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.971-627T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,036 control chromosomes in the GnomAD database, including 39,256 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 0.72 ( 39256 hom., cov: 32)

Consequence

ACO1
NM_002197.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.294

Publications

12 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=-0.96).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 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.971-627T>A	intron	N/A	NP_002188.1	P21399
ACO1	NM_001278352.2		c.971-627T>A	intron	N/A	NP_001265281.1	P21399
ACO1	NM_001362840.2		c.971-627T>A	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.971-627T>A	intron	N/A	ENSP00000309477.5	P21399
ACO1	ENST00000963208.1		c.1001-627T>A	intron	N/A	ENSP00000633267.1
ACO1	ENST00000379923.5	TSL:5	c.971-627T>A	intron	N/A	ENSP00000369255.1	P21399

Frequencies

GnomAD3 genomes

AF:

0.718

AC:

109057

AN:

151918

Hom.:

39216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.746

Gnomad AMI

AF:

0.832

Gnomad AMR

AF:

0.686

Gnomad ASJ

AF:

0.813

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.740

Gnomad FIN

AF:

0.636

Gnomad MID

AF:

0.807

Gnomad NFE

AF:

0.718

Gnomad OTH

AF:

0.733

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

GnomAD4 genome

AF:

0.718

AC:

109148

AN:

152036

Hom.:

39256

Cov.:

AF XY:

0.715

AC XY:

53123

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.746

AC:

30940

AN:

41456

American (AMR)

AF:

0.686

AC:

10474

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

2819

AN:

3468

East Asian (EAS)

AF:

0.631

AC:

3265

AN:

5174

South Asian (SAS)

AF:

0.739

AC:

3565

AN:

4822

European-Finnish (FIN)

AF:

0.636

AC:

6700

AN:

10538

Middle Eastern (MID)

AF:

0.806

AC:

237

AN:

294

European-Non Finnish (NFE)

AF:

0.718

AC:

48835

AN:

67986

Other (OTH)

AF:

0.735

AC:

1554

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1550

3100

4651

6201

7751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.716

Hom.:

4867

Bravo

AF:

0.719

Asia WGS

AF:

0.698

AC:

2425

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.2

(source)

DANN

Benign

0.63

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over