rs3780473

Positions:

• chr9-32425912-A-C
• chr9-32425912-A-G
• chr9-32425912-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002197.3(ACO1):​c.1263A>C​(p.Glu421Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACO1 NM_002197.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32991064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO1	NM_002197.3	c.1263A>C	p.Glu421Asp	missense_variant	11/21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.1263A>C	p.Glu421Asp	missense_variant	12/22		NP_001265281.1
ACO1	NM_001362840.2	c.1263A>C	p.Glu421Asp	missense_variant	12/22		NP_001349769.1
ACO1	XM_047423430.1	c.1287A>C	p.Glu429Asp	missense_variant	11/21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.1263A>C	p.Glu421Asp	missense_variant	11/21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.1263A>C	p.Glu421Asp	missense_variant	12/22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.1263A>C	p.Glu421Asp	missense_variant	12/22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.82	L;L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.29	.;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.11
MutPred		0.34		Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);
MVP		0.29
MPC		0.21
ClinPred		0.14	T
GERP RS		0.72
Varity_R		0.30
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

Other links and lift over

dbSNP: rs3780473; hg19: chr9-32425910;