Genetic Variant NM_002197.3:c.666T>C (chr9-32419045-T-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6_ModerateBP7

The NM_002197.3(ACO1):c.666T>C(p.Gly222Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,601,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

ACO1
NM_002197.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.196

Publications

2 publications found

Variant links:

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]

ACO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 9-32419045-T-C is Benign according to our data. Variant chr9-32419045-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3388109.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.196 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002197.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACO1	NM_002197.3	MANE Select	c.666T>C	p.Gly222Gly	synonymous	Exon 7 of 21	NP_002188.1	P21399
ACO1	NM_001278352.2		c.666T>C	p.Gly222Gly	synonymous	Exon 8 of 22	NP_001265281.1	P21399
ACO1	NM_001362840.2		c.666T>C	p.Gly222Gly	synonymous	Exon 8 of 22	NP_001349769.1	P21399

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACO1	ENST00000309951.8	TSL:1 MANE Select	c.666T>C	p.Gly222Gly	synonymous	Exon 7 of 21	ENSP00000309477.5	P21399
ACO1	ENST00000963208.1		c.696T>C	p.Gly232Gly	synonymous	Exon 7 of 21	ENSP00000633267.1
ACO1	ENST00000379923.5	TSL:5	c.666T>C	p.Gly222Gly	synonymous	Exon 8 of 22	ENSP00000369255.1	P21399

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000284

AC:

AN:

242898

AF XY:

0.000259

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000542

Gnomad OTH exome

AF:

0.000516

GnomAD4 exome

AF:

0.000515

AC:

747

AN:

1449146

Hom.:

Cov.:

AF XY:

0.000493

AC XY:

355

AN XY:

720020

show subpopulations

African (AFR)

AF:

0.0000607

AC:

AN:

32960

American (AMR)

AF:

0.000162

AC:

AN:

43172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25696

East Asian (EAS)

AF:

0.00

AC:

AN:

39068

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53200

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000649

AC:

717

AN:

1104932

Other (OTH)

AF:

0.000234

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000269

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000508

Hom.:

Bravo

AF:

0.000283

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.9

(source)

DANN

Benign

0.72

PhyloP100

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over