9-32419166-A-T

Variant names:

• chr9-32419166-A-T
• rs745813050
• NM_002197.3:c.787A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002197.3(ACO1):​c.787A>T​(p.Thr263Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000557 in 1,437,152 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: ACO1 NM_002197.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO1	NM_002197.3	c.787A>T	p.Thr263Ser	missense_variant	Exon 7 of 21	ENST00000309951.8	NP_002188.1
ACO1	NM_001278352.2	c.787A>T	p.Thr263Ser	missense_variant	Exon 8 of 22		NP_001265281.1
ACO1	NM_001362840.2	c.787A>T	p.Thr263Ser	missense_variant	Exon 8 of 22		NP_001349769.1
ACO1	XM_047423430.1	c.811A>T	p.Thr271Ser	missense_variant	Exon 7 of 21		XP_047279386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO1	ENST00000309951.8	c.787A>T	p.Thr263Ser	missense_variant	Exon 7 of 21	1	NM_002197.3	ENSP00000309477.5
ACO1	ENST00000379923.5	c.787A>T	p.Thr263Ser	missense_variant	Exon 8 of 22	5		ENSP00000369255.1
ACO1	ENST00000541043.5	c.787A>T	p.Thr263Ser	missense_variant	Exon 8 of 22	5		ENSP00000438733.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000432 AC: 1 AN: 231622 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000936

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1437152 Hom.: 0 Cov.: 30 AF XY: 0.00000700 AC XY: 5 AN XY: 714548

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: 0.00000728

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.787A>T (p.T263S) alteration is located in exon 7 (coding exon 6) of the ACO1 gene. This alteration results from a A to T substitution at nucleotide position 787, causing the threonine (T) at amino acid position 263 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;.;.
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.4	M;M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	.;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.080	.;T;T
Sift4G	Uncertain	0.054	T;T;T
Polyphen		0.68	P;P;P
Vest4		0.45
MutPred		0.59		Gain of MoRF binding (P = 0.1498);Gain of MoRF binding (P = 0.1498);Gain of MoRF binding (P = 0.1498);
MVP		0.64
MPC		0.56
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.72
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs745813050; hg19: chr9-32419164;