12-109139539-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001093.4(ACACB):c.134A>G(p.Gln45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,614,128 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0770

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACACB
• BP4: Computational evidence support a benign effect (MetaRNN=0.008687645).
• BP6: Variant 12-109139539-A-G is Benign according to our data. Variant chr12-109139539-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 789325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr12-109139539-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACB	NM_001093.4	c.134A>G	p.Gln45Arg	missense_variant	2/53	ENST00000338432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACB	ENST00000338432.12	c.134A>G	p.Gln45Arg	missense_variant	2/53	1	NM_001093.4	P1
ACACB	ENST00000377848.7	c.134A>G	p.Gln45Arg	missense_variant	1/52	1		P1
ACACB	ENST00000539864.1	c.59A>G	p.Gln20Arg	missense_variant	2/2	3
ACACB	ENST00000377854.9	c.-3869A>G		5_prime_UTR_variant	1/47	5

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00215 AC: 541 AN: 251482 Hom.: 0 AF XY: 0.00186 AC XY: 253 AN XY: 135914

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00340

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00369 AC: 5398 AN: 1461894 Hom.: 17 Cov.: 30 AF XY: 0.00338 AC XY: 2458 AN XY: 727248

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00334

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74424

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00312 Hom.: 1

Bravo AF: 0.00239

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00205 AC: 249

EpiCase AF: 0.00262

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

ACACB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

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	0.066
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	8.3
Dann	Benign	0.78
DEOGEN2	Benign	0.35	T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.11	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.42	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.82	N;D;N
REVEL	Benign	0.17
Sift	Benign	0.39	T;T;T
Sift4G	Benign	1.0	T;D;T
Polyphen		0.0	B;.;B
Vest4		0.11
MVP		0.52
MPC		0.26
ClinPred		0.0045	T
GERP RS		0.15
Varity_R		0.050
gMVP		0.053

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: rs139767464; hg19: chr12-109577344;