12-109167925-C-T

Variant names:

• chr12-109167925-C-T
• rs4766516
• NM_001093.4:c.816C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001093.4(ACACB):​c.816C>T​(p.Ala272Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,613,306 control chromosomes in the GnomAD database, including 36,864 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A272A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3042 hom., cov: 28)
  • Exomes 𝑓: 0.21 (33822 hom.)
• Consequence: ACACB NM_001093.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.89
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP7: Synonymous conserved (PhyloP=-2.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	NM_001093.4	MANE Select	c.816C>T	p.Ala272Ala	synonymous	Exon 4 of 53	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.816C>T	p.Ala272Ala	synonymous	Exon 5 of 54	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.816C>T	p.Ala272Ala	synonymous	Exon 4 of 53	NP_001399664.1	O00763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.816C>T	p.Ala272Ala	synonymous	Exon 4 of 53	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.816C>T	p.Ala272Ala	synonymous	Exon 3 of 52	ENSP00000367079.3	O00763-1
	ACACB	ENST00000377854.9	TSL:5	c.-3187C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 47	ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27191 AN: 151610 Hom.: 3039 Cov.: 28

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.233 AC: 58490 AN: 251142 AF XY: 0.233

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.549

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.206 AC: 301470 AN: 1461578 Hom.: 33822 Cov.: 34 AF XY: 0.208 AC XY: 150888 AN XY: 727082

African (AFR) AF: 0.0638 AC: 2136 AN: 33476

American (AMR) AF: 0.251 AC: 11229 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6073 AN: 26130

East Asian (EAS) AF: 0.507 AC: 20114 AN: 39638

South Asian (SAS) AF: 0.251 AC: 21649 AN: 86250

European-Finnish (FIN) AF: 0.219 AC: 11677 AN: 53414

Middle Eastern (MID) AF: 0.144 AC: 828 AN: 5764

European-Non Finnish (NFE) AF: 0.194 AC: 215175 AN: 1111862

Other (OTH) AF: 0.209 AC: 12589 AN: 60366

GnomAD4 genome AF: 0.179 AC: 27204 AN: 151728 Hom.: 3042 Cov.: 28 AF XY: 0.184 AC XY: 13634 AN XY: 74096

African (AFR) AF: 0.0708 AC: 2931 AN: 41402

American (AMR) AF: 0.217 AC: 3295 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 818 AN: 3470

East Asian (EAS) AF: 0.529 AC: 2691 AN: 5084

South Asian (SAS) AF: 0.265 AC: 1268 AN: 4792

European-Finnish (FIN) AF: 0.221 AC: 2329 AN: 10538

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13239 AN: 67914

Other (OTH) AF: 0.186 AC: 392 AN: 2106

Alfa AF: 0.183 Hom.: 1727

Bravo AF: 0.175

Asia WGS AF: 0.346 AC: 1205 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.32
DANN	Benign	0.64
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4766516; hg19: chr12-109605730; COSMIC: COSV58131765; COSMIC: COSV58131765;