12-109232663-T-C

Position:

• chr12-109232663-T-C

Variant summary

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

The NM_001093.4(ACACB):​c.4002-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,613,308 control chromosomes in the GnomAD database, including 642,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (63689 hom., cov: 32)
  • Exomes 𝑓: 0.89 (578467 hom.)
• Consequence: ACACB NM_001093.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004181
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.905

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]

ACACB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACACB	NM_001093.4	c.4002-6T>C		splice_region_variant, intron_variant		ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.4002-6T>C		splice_region_variant, intron_variant		1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.4002-6T>C		splice_region_variant, intron_variant		1		ENSP00000367079.3
ACACB	ENST00000377854.9	c.-1-6T>C		splice_region_variant, intron_variant		5		ENSP00000367085.6
ACACB	ENST00000538526.5	n.-7T>C		upstream_gene_variant		5		ENSP00000443281.1

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138861 AN: 152128 Hom.: 63640 Cov.: 32

Gnomad AFR AF: 0.978

Gnomad AMI AF: 0.836

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.894

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.898

Gnomad OTH AF: 0.913

GnomAD3 exomes AF: 0.883 AC: 220844 AN: 249990 Hom.: 98073 AF XY: 0.878 AC XY: 118529 AN XY: 135062

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.938

Gnomad ASJ exome AF: 0.904

Gnomad EAS exome AF: 0.739

Gnomad SAS exome AF: 0.792

Gnomad FIN exome AF: 0.897

Gnomad NFE exome AF: 0.896

Gnomad OTH exome AF: 0.892

GnomAD4 exome AF: 0.888 AC: 1297998 AN: 1461062 Hom.: 578467 Cov.: 56 AF XY: 0.886 AC XY: 643621 AN XY: 726822

Gnomad4 AFR exome AF: 0.983

Gnomad4 AMR exome AF: 0.936

Gnomad4 ASJ exome AF: 0.902

Gnomad4 EAS exome AF: 0.669

Gnomad4 SAS exome AF: 0.794

Gnomad4 FIN exome AF: 0.894

Gnomad4 NFE exome AF: 0.898

Gnomad4 OTH exome AF: 0.889

GnomAD4 genome AF: 0.913 AC: 138965 AN: 152246 Hom.: 63689 Cov.: 32 AF XY: 0.910 AC XY: 67729 AN XY: 74414

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.925

Gnomad4 ASJ AF: 0.894

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.789

Gnomad4 FIN AF: 0.899

Gnomad4 NFE AF: 0.898

Gnomad4 OTH AF: 0.909

Alfa AF: 0.904 Hom.: 80465

Bravo AF: 0.919

Asia WGS AF: 0.768 AC: 2672 AN: 3478

EpiCase AF: 0.900

EpiControl AF: 0.897

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.022
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: rs3742027; hg19: chr12-109670468; COSMIC: COSV58135002; COSMIC: COSV58135002;