Genetic Variant NM_002197.3:c.*2518T>C (chr9-32452629-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.*2518T>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 0.175 in 151,850 control chromosomes in the GnomAD database, including 2,618 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 0.17 ( 2618 hom., cov: 31)

Exomes 𝑓: 0.14 ( 0 hom. )

Consequence

ACO1
NM_002197.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.370

Publications

4 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=-0.94).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3 link	c.*2518T>C	3_prime_UTR_variant	Exon 21 of 21	ENST00000309951.8	NP_002188.1	P21399V9HWB7
ACO1	NM_001278352.2 link	c.*2518T>C	3_prime_UTR_variant	Exon 22 of 22		NP_001265281.1	P21399V9HWB7Q9HBB2
ACO1	NM_001362840.2 link	c.*2518T>C	3_prime_UTR_variant	Exon 22 of 22		NP_001349769.1
ACO1	XM_047423430.1 link	c.*2518T>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.*2518T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_002197.3	ENSP00000309477.5		P21399

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26539

AN:

151718

Hom.:

2617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.125

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.0622

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.159

GnomAD4 exome

AF:

0.143

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

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)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.143

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.175

AC:

26557

AN:

151836

Hom.:

2618

Cov.:

AF XY:

0.177

AC XY:

13111

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.123

AC:

5073

AN:

41404

American (AMR)

AF:

0.125

AC:

1903

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

620

AN:

3468

East Asian (EAS)

AF:

0.0624

AC:

322

AN:

5162

South Asian (SAS)

AF:

0.327

AC:

1571

AN:

4802

European-Finnish (FIN)

AF:

0.203

AC:

2139

AN:

10544

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.212

AC:

14431

AN:

67912

Other (OTH)

AF:

0.157

AC:

331

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1072

2145

3217

4290

5362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.195

Hom.:

4459

Bravo

AF:

0.162

Asia WGS

AF:

0.183

AC:

638

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.48

(source)

DANN

Benign

0.59

PhyloP100

-0.37

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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NM_002197.3:c.*2518T>C

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