9-32418485-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002197.3(ACO1):c.632T>C(p.Ile211Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACO1
NM_002197.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.97

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 6 of 21	ENST00000309951.8	NP_002188.1	P21399V9HWB7
ACO1	NM_001278352.2 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 7 of 22		NP_001265281.1	P21399V9HWB7Q9HBB2
ACO1	NM_001362840.2 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 7 of 22		NP_001349769.1
ACO1	XM_047423430.1 link	c.656T>C	p.Ile219Thr	missense_variant	Exon 6 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACO1	ENST00000309951.8 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 6 of 21	1	NM_002197.3	ENSP00000309477.5	P21399
ACO1	ENST00000379923.5 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 7 of 22	5		ENSP00000369255.1	P21399
ACO1	ENST00000541043.5 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 7 of 22	5		ENSP00000438733.2	P21399

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250924

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461256

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111494

Other (OTH)

AF:

0.00

AC:

AN:

60378

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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.632T>C (p.I211T) alteration is located in exon 6 (coding exon 5) of the ACO1 gene. This alteration results from a T to C substitution at nucleotide position 632, causing the isoleucine (I) at amino acid position 211 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;.

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

4.0

H;H;H

PhyloP100

8.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.7

.;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.93

MutPred

0.72

Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);

MVP

0.64

MPC

0.96

ClinPred

1.0

GERP RS

5.8

Varity_R

0.92

gMVP

0.91

Mutation Taster

=39/61

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over