Genetic Variant NM_023928.5:c.352A>G (chr12-125076605-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_023928.5(AACS):c.352A>G(p.Ile118Val) variant causes a missense change. The variant allele was found at a frequency of 0.149 in 1,613,700 control chromosomes in the GnomAD database, including 19,958 homozygotes. 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: 𝑓 0.19 ( 3131 hom., cov: 32)

Exomes 𝑓: 0.15 ( 16827 hom. )

Consequence

AACS
NM_023928.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.52

Publications

17 publications found

Variant links:

Genes affected

AACS (HGNC:21298): (acetoacetyl-CoA synthetase) Predicted to enable acetoacetate-CoA ligase activity. Predicted to be involved in positive regulation of insulin secretion. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

AACS links:

LOC105370052 (HGNC:):

LOC105370052 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004404962).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AACS	NM_023928.5 link	c.352A>G	p.Ile118Val	missense_variant	Exon 3 of 18	ENST00000316519.11	NP_076417.2	Q86V21-1A0A024RBV2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AACS	ENST00000316519.11 link	c.352A>G	p.Ile118Val	missense_variant	Exon 3 of 18	1	NM_023928.5	ENSP00000324842.6		Q86V21-1
AACS	ENST00000418937.6 link	n.352A>G		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000416461.2		E7EW25

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28747

AN:

152004

Hom.:

3122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.0440

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.217

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.224

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.196

GnomAD2 exomes

AF:

0.161

AC:

40469

AN:

251408

AF XY:

0.162

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.214

Gnomad EAS exome

AF:

0.129

Gnomad FIN exome

AF:

0.0900

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.173

GnomAD4 exome

AF:

0.145

AC:

212018

AN:

1461576

Hom.:

16827

Cov.:

AF XY:

0.147

AC XY:

107057

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.313

AC:

10466

AN:

33450

American (AMR)

AF:

0.160

AC:

7162

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5529

AN:

26126

East Asian (EAS)

AF:

0.157

AC:

6214

AN:

39692

South Asian (SAS)

AF:

0.221

AC:

19050

AN:

86250

European-Finnish (FIN)

AF:

0.0910

AC:

4859

AN:

53392

Middle Eastern (MID)

AF:

0.238

AC:

1370

AN:

5760

European-Non Finnish (NFE)

AF:

0.133

AC:

147461

AN:

1111828

Other (OTH)

AF:

0.164

AC:

9907

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

9511

19023

28534

38046

47557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5434

10868

16302

21736

27170

<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:

0.189

AC:

28786

AN:

152124

Hom.:

3131

Cov.:

AF XY:

0.189

AC XY:

14054

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.304

AC:

12614

AN:

41460

American (AMR)

AF:

0.181

AC:

2764

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

753

AN:

3470

East Asian (EAS)

AF:

0.134

AC:

695

AN:

5172

South Asian (SAS)

AF:

0.225

AC:

1085

AN:

4824

European-Finnish (FIN)

AF:

0.0924

AC:

979

AN:

10592

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.138

AC:

9363

AN:

68012

Other (OTH)

AF:

0.196

AC:

415

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1160

2321

3481

4642

5802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.158

Hom.:

8899

Bravo

AF:

0.201

TwinsUK

AF:

0.128

AC:

475

ALSPAC

AF:

0.131

AC:

505

ESP6500AA

AF:

0.293

AC:

1292

ESP6500EA

AF:

0.143

AC:

1229

ExAC

AF:

0.164

AC:

19945

Asia WGS

AF:

0.191

AC:

660

AN:

3478

EpiCase

AF:

0.144

EpiControl

AF:

0.151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.0

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.12

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.2

PhyloP100

5.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.070

REVEL

Benign

0.13

Sift

Benign

0.76

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.019

MPC

0.095

ClinPred

0.0030

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.023

gMVP

0.29

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over