chr9-32405591-G-T

Variant names:

• chr9-32405591-G-T
• rs41313772
• NM_002197.3:c.85G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002197.3(ACO1):​c.85G>T​(p.Asp29Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,609,492 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: ACO1 NM_002197.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.48

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016622573).
• 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.85G>T	p.Asp29Tyr	missense_variant	Exon 2 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.85G>T	p.Asp29Tyr	missense_variant	Exon 3 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.85G>T	p.Asp29Tyr	missense_variant	Exon 3 of 22		NP_001349769.1
ACO1	XM_047423430.1	c.109G>T	p.Asp37Tyr	missense_variant	Exon 2 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.85G>T	p.Asp29Tyr	missense_variant	Exon 2 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.85G>T	p.Asp29Tyr	missense_variant	Exon 3 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.85G>T	p.Asp29Tyr	missense_variant	Exon 3 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000911 AC: 227 AN: 249194 Hom.: 1 AF XY: 0.000942 AC XY: 127 AN XY: 134798

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000331

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00141 AC: 2049 AN: 1457186 Hom.: 3 Cov.: 29 AF XY: 0.00136 AC XY: 988 AN XY: 725152

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000786

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74474

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00202

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 12, 2023

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	Uncertain	0.39
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.78	D;D;D
Eigen	Benign	-0.038
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.3	.;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.011	.;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.0030	B;B;B
Vest4		0.49
MVP		0.36
MPC		0.28
ClinPred		0.083	T
GERP RS		4.9
Varity_R		0.61
gMVP		0.73

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

Other links and lift over

dbSNP: rs41313772; hg19: chr9-32405589;