12-109232663-T-C

Variant names:

• chr12-109232663-T-C
• rs3742027
• NM_001093.4:c.4002-6T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• isolated cleft palate

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ACACB	NM_001093.4	c.4002-6T>C		splice_region_variant, intron_variant	Intron 28 of 52	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.4002-6T>C		splice_region_variant, intron_variant	Intron 28 of 52	1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.4002-6T>C		splice_region_variant, intron_variant	Intron 27 of 51	1		ENSP00000367079.3
ACACB	ENST00000377854.9	c.-1-6T>C		splice_region_variant, intron_variant	Intron 27 of 46	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

GnomAD2 exomes AF: 0.883 AC: 220844 AN: 249990 AF XY: 0.878

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 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

African (AFR) AF: 0.983 AC: 32874 AN: 33454

American (AMR) AF: 0.936 AC: 41808 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 23514 AN: 26068

East Asian (EAS) AF: 0.669 AC: 26517 AN: 39662

South Asian (SAS) AF: 0.794 AC: 68412 AN: 86154

European-Finnish (FIN) AF: 0.894 AC: 47685 AN: 53356

Middle Eastern (MID) AF: 0.889 AC: 5124 AN: 5766

European-Non Finnish (NFE) AF: 0.898 AC: 998394 AN: 1111586

Other (OTH) AF: 0.889 AC: 53670 AN: 60358

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

African (AFR) AF: 0.978 AC: 40654 AN: 41558

American (AMR) AF: 0.925 AC: 14155 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 3105 AN: 3472

East Asian (EAS) AF: 0.717 AC: 3707 AN: 5170

South Asian (SAS) AF: 0.789 AC: 3800 AN: 4816

European-Finnish (FIN) AF: 0.899 AC: 9526 AN: 10600

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.898 AC: 61071 AN: 68018

Other (OTH) AF: 0.909 AC: 1918 AN: 2110

Alfa AF: 0.905 Hom.: 109392

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
PhyloP100		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3742027; hg19: chr12-109670468; COSMIC: COSV58135002; COSMIC: COSV58135002;