Genetic Variant NM_002197.3:c.367G>A (chr9-32408614-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002197.3(ACO1):c.367G>A(p.Val123Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,614,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 3 hom. )

Consequence

ACO1
NM_002197.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.23

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02454874).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3 link	c.367G>A	p.Val123Ile	missense_variant	Exon 4 of 21	ENST00000309951.8	NP_002188.1	P21399V9HWB7
ACO1	NM_001278352.2 link	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22		NP_001265281.1	P21399V9HWB7Q9HBB2
ACO1	NM_001362840.2 link	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22		NP_001349769.1
ACO1	XM_047423430.1 link	c.391G>A	p.Val131Ile	missense_variant	Exon 4 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACO1	ENST00000309951.8 link	c.367G>A	p.Val123Ile	missense_variant	Exon 4 of 21	1	NM_002197.3	ENSP00000309477.5	P21399
ACO1	ENST00000379923.5 link	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22	5		ENSP00000369255.1	P21399
ACO1	ENST00000541043.5 link	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22	5		ENSP00000438733.2	P21399

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00135

AC:

340

AN:

251414

Hom.:

AF XY:

0.00146

AC XY:

198

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00235

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00233

AC:

3404

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1664

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000742

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00283

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00136

AC:

207

AN:

152318

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00126

AC:

153

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;.

M_CAP

Benign

0.0072

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.88

.;N;N

REVEL

Benign

0.15

Sift

Benign

0.11

.;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.33

MVP

0.37

MPC

0.19

ClinPred

0.032

GERP RS

5.7

Varity_R

0.25

gMVP

0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over