dbSNP rs10970986: ACO1:c.*3169T>C (chr9-32453280-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.*3169T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 150,158 control chromosomes in the GnomAD database, including 4,483 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 0.22 ( 4483 hom., cov: 28)

Failed GnomAD Quality Control

Consequence

ACO1
NM_002197.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.489

Publications

13 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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ACO1	NM_002197.3 link	c.*3169T>C	3_prime_UTR_variant	Exon 21 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2 link	c.*3169T>C	3_prime_UTR_variant	Exon 22 of 22		NP_001265281.1
ACO1	NM_001362840.2 link	c.*3169T>C	3_prime_UTR_variant	Exon 22 of 22		NP_001349769.1
ACO1	XM_047423430.1 link	c.*3169T>C	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.*3169T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_002197.3	ENSP00000309477.5

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33438

AN:

150042

Hom.:

4472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.262

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.280

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.263

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

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:

0.223

AC:

33448

AN:

150158

Hom.:

4483

Cov.:

AF XY:

0.220

AC XY:

16126

AN XY:

73180

show subpopulations

African (AFR)

AF:

0.0597

AC:

2428

AN:

40690

American (AMR)

AF:

0.262

AC:

3941

AN:

15056

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

971

AN:

3464

East Asian (EAS)

AF:

0.297

AC:

1515

AN:

5094

South Asian (SAS)

AF:

0.197

AC:

937

AN:

4766

European-Finnish (FIN)

AF:

0.229

AC:

2301

AN:

10058

Middle Eastern (MID)

AF:

0.288

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.301

AC:

20376

AN:

67754

Other (OTH)

AF:

0.273

AC:

567

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1224

2448

3673

4897

6121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.265

Hom.:

12385

Bravo

AF:

0.218

Asia WGS

AF:

0.260

AC:

903

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.6

(source)

DANN

Benign

0.50

PhyloP100

0.49

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