rs11549081

Positions:

• chr12-125076605-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3131 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16827 hom.)
• Consequence: AACS NM_023928.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.52

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]

LOC105370052 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
AACS	NM_023928.5	c.352A>G	p.Ile118Val	missense_variant	3/18	ENST00000316519.11
LOC105370052	XR_001749365.2	n.194+4885T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AACS	ENST00000316519.11	c.352A>G	p.Ile118Val	missense_variant	3/18	1	NM_023928.5	P1
AACS	ENST00000418937.6	c.352A>G	p.Ile118Val	missense_variant, NMD_transcript_variant	3/9	2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28747 AN: 152004 Hom.: 3122 Cov.: 32

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

GnomAD3 exomes AF: 0.161 AC: 40469 AN: 251408 Hom.: 3647 AF XY: 0.162 AC XY: 22070 AN XY: 135878

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 SAS exome AF: 0.224

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.: 31 AF XY: 0.147 AC XY: 107057 AN XY: 727076

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.0910

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.189 AC: 28786 AN: 152124 Hom.: 3131 Cov.: 32 AF XY: 0.189 AC XY: 14054 AN XY: 74360

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.0924

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.196

Alfa AF: 0.153 Hom.: 3921

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	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.0
DANN	Benign	0.31
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.13
Sift	Benign	0.76	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.095
ClinPred		0.0030	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.29

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: rs11549081; hg19: chr12-125561151; COSMIC: COSV55538343;