dbSNP rs10970985: ACO1:c.*3010C>G (chr9-32453121-C-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.*3010C>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 0.621 in 151,890 control chromosomes in the GnomAD database, including 29,388 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 ( 29388 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACO1
NM_002197.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.25

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=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ACO1	NM_002197.3 link	c.*3010C>G	3_prime_UTR_variant	Exon 21 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2 link	c.*3010C>G	3_prime_UTR_variant	Exon 22 of 22		NP_001265281.1
ACO1	NM_001362840.2 link	c.*3010C>G	3_prime_UTR_variant	Exon 22 of 22		NP_001349769.1
ACO1	XM_047423430.1 link	c.*3010C>G	3_prime_UTR_variant	Exon 21 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8 link	c.*3010C>G		3_prime_UTR_variant	Exon 21 of 21	1	NM_002197.3	ENSP00000309477.5

Frequencies

GnomAD3 genomes

AF:

0.621

AC:

94181

AN:

151772

Hom.:

29341

Cov.:

show subpopulations

Gnomad AFR

AF:

0.558

Gnomad AMI

AF:

0.624

Gnomad AMR

AF:

0.608

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.632

Gnomad FIN

AF:

0.630

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.594

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.621

AC:

94278

AN:

151890

Hom.:

29388

Cov.:

AF XY:

0.620

AC XY:

46000

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.558

AC:

23116

AN:

41414

American (AMR)

AF:

0.608

AC:

9280

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.614

AC:

2126

AN:

3464

East Asian (EAS)

AF:

0.582

AC:

3000

AN:

5152

South Asian (SAS)

AF:

0.631

AC:

3041

AN:

4816

European-Finnish (FIN)

AF:

0.630

AC:

6612

AN:

10500

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45105

AN:

67954

Other (OTH)

AF:

0.599

AC:

1266

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1811

3621

5432

7242

9053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.554

Hom.:

1623

Bravo

AF:

0.616

Asia WGS

AF:

0.597

AC:

2076

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.046

(source)

DANN

Benign

0.37

PhyloP100

-2.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over