chr9-32408614-G-A

Variant names:

• chr9-32408614-G-A
• rs41304757
• NM_002197.3:c.367G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23
• Publications: 10 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.367G>A	p.Val123Ile	missense_variant	Exon 4 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22		NP_001349769.1
ACO1	XM_047423430.1	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	Appris	UniProt
ACO1	ENST00000309951.8	c.367G>A	p.Val123Ile	missense_variant	Exon 4 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.367G>A	p.Val123Ile	missense_variant	Exon 5 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152200 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00135 AC: 340 AN: 251414 AF XY: 0.00146

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 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.: 3 Cov.: 31 AF XY: 0.00229 AC XY: 1664 AN XY: 727220

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86254

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00283 AC: 3147 AN: 1111978

Other (OTH) AF: 0.00205 AC: 124 AN: 60396

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74494

African (AFR) AF: 0.000602 AC: 25 AN: 41556

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00147

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.97	D;.;.
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		4.2
PrimateAI	Uncertain	0.50	T
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	T
GERP RS		5.7
Varity_R		0.25
gMVP		0.50
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs41304757; hg19: chr9-32408612;