Genetic Variant NM_002197.3:c.*1035A>G (chr9-32451146-A-G) – 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.*1035A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 151,888 control chromosomes in the GnomAD database, including 29,205 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 0.62 ( 29202 hom., cov: 31)

Exomes 𝑓: 0.88 ( 3 hom. )

Consequence

ACO1
NM_002197.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.10

Publications

21 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=-0.97).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 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
ACO1	NM_002197.3	MANE Select	c.*1035A>G	3_prime_UTR	Exon 21 of 21	NP_002188.1
ACO1	NM_001278352.2		c.*1035A>G	3_prime_UTR	Exon 22 of 22	NP_001265281.1
ACO1	NM_001362840.2		c.*1035A>G	3_prime_UTR	Exon 22 of 22	NP_001349769.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO1	ENST00000309951.8	TSL:1 MANE Select	c.*1035A>G		3_prime_UTR	Exon 21 of 21	ENSP00000309477.5

Frequencies

GnomAD3 genomes

AF:

0.618

AC:

93780

AN:

151764

Hom.:

29160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.545

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.606

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.583

Gnomad SAS

AF:

0.635

Gnomad FIN

AF:

0.635

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.665

Gnomad OTH

AF:

0.593

GnomAD4 exome

AF:

0.875

AC:

AN:

Hom.:

Cov.:

AF XY:

0.875

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

GnomAD4 genome

AF:

0.618

AC:

93871

AN:

151880

Hom.:

29202

Cov.:

AF XY:

0.617

AC XY:

45809

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.546

AC:

22585

AN:

41386

American (AMR)

AF:

0.606

AC:

9262

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

2131

AN:

3470

East Asian (EAS)

AF:

0.583

AC:

2998

AN:

5140

South Asian (SAS)

AF:

0.634

AC:

3054

AN:

4818

European-Finnish (FIN)

AF:

0.635

AC:

6675

AN:

10512

Middle Eastern (MID)

AF:

0.558

AC:

163

AN:

292

European-Non Finnish (NFE)

AF:

0.665

AC:

45173

AN:

67960

Other (OTH)

AF:

0.599

AC:

1262

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1825

3650

5475

7300

9125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<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:

0.650

Hom.:

141091

Bravo

AF:

0.612

Asia WGS

AF:

0.608

AC:

2115

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.040

(source)

DANN

Benign

0.37

PhyloP100

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over