12-109139971-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001093.4(ACACB):c.566G>A(p.Arg189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,860 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

Genes affected

ACACB (HGNC:85): (acetyl-CoA carboxylase beta) Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. [provided by RefSeq, Oct 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACACB
• BP4: Computational evidence support a benign effect (MetaRNN=0.015202165).
• BP6: Variant 12-109139971-G-A is Benign according to our data. Variant chr12-109139971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3044486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACB	NM_001093.4	c.566G>A	p.Arg189Gln	missense_variant	2/53	ENST00000338432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACB	ENST00000338432.12	c.566G>A	p.Arg189Gln	missense_variant	2/53	1	NM_001093.4	P1
ACACB	ENST00000377848.7	c.566G>A	p.Arg189Gln	missense_variant	1/52	1		P1
ACACB	ENST00000377854.9	c.-3437G>A		5_prime_UTR_variant	1/47	5
ACACB	ENST00000546328.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152170 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 250238 Hom.: 0 AF XY: 0.00127 AC XY: 172 AN XY: 135320

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00159

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.00153 AC: 2229 AN: 1461572 Hom.: 4 Cov.: 34 AF XY: 0.00154 AC XY: 1119 AN XY: 727084

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152288 Hom.: 3 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74452

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00205 Hom.: 3

Bravo AF: 0.000994

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00124

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACACB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	0.072
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.065
Sift	Benign	0.15	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.98	D;D
Vest4		0.16
MVP		0.31
MPC		0.28
ClinPred		0.017	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs118018469; hg19: chr12-109577776; COSMIC: COSV100622990; COSMIC: COSV100622990;