chr9-32407400-G-C

Variant names:

• chr9-32407400-G-C
• NM_002197.3:c.237G>C

Variant summary

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

The NM_002197.3(ACO1):​c.237G>C​(p.Lys79Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACO1 NM_002197.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.587

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=0.3721102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.237G>C	p.Lys79Asn	missense_variant	Exon 3 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.237G>C	p.Lys79Asn	missense_variant	Exon 4 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.237G>C	p.Lys79Asn	missense_variant	Exon 4 of 22		NP_001349769.1
ACO1	XM_047423430.1	c.261G>C	p.Lys87Asn	missense_variant	Exon 3 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.237G>C	p.Lys79Asn	missense_variant	Exon 3 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.237G>C	p.Lys79Asn	missense_variant	Exon 4 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.237G>C	p.Lys79Asn	missense_variant	Exon 4 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T;.;.
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	.;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0090	.;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.13	B;B;B
Vest4		0.28
MutPred		0.48		Loss of methylation at K79 (P = 0.0126);Loss of methylation at K79 (P = 0.0126);Loss of methylation at K79 (P = 0.0126);
MVP		0.38
MPC		0.34
ClinPred		0.98	D
GERP RS		0.14
Varity_R		0.49
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-32407398;