NM_002197.3:c.367G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002197.3(ACO1):​c.367G>T​(p.Val123Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V123I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACO1 NM_002197.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.367G>T	p.Val123Leu	missense_variant	Exon 4 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.367G>T	p.Val123Leu	missense_variant	Exon 5 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.367G>T	p.Val123Leu	missense_variant	Exon 5 of 22		NP_001349769.1
ACO1	XM_047423430.1	c.391G>T	p.Val131Leu	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>T	p.Val123Leu	missense_variant	Exon 4 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.367G>T	p.Val123Leu	missense_variant	Exon 5 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.367G>T	p.Val123Leu	missense_variant	Exon 5 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	4.5	H;H;H
PhyloP100		4.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.063	B;B;B
Vest4		0.78
MutPred		0.80		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.43
MPC		0.27
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.74
Mutation Taster		=41/59	disease causing

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; COSMIC: COSV59376485;