rs4766587

Variant names:

• chr12-109247525-G-A
• rs4766587
• NM_001093.4:c.5572-81G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001093.4(ACACB):​c.5572-81G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 919,252 control chromosomes in the GnomAD database, including 34,224 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.

• Frequency:
  • Genomes: 𝑓 0.23 (4698 hom., cov: 30)
  • Exomes 𝑓: 0.27 (29526 hom.)
• Consequence: ACACB NM_001093.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 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.5572-81G>A		intron	N/A	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.5572-81G>A		intron	N/A	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.5572-81G>A		intron	N/A	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.5572-81G>A		intron	N/A	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.5572-81G>A		intron	N/A	ENSP00000367079.3	O00763-1
	ACACB	ENST00000377854.9	TSL:5	c.1570-81G>A		intron	N/A	ENSP00000367085.6	F8W8T8

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34899 AN: 150760 Hom.: 4701 Cov.: 30

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.266 AC: 204445 AN: 768378 Hom.: 29526 AF XY: 0.267 AC XY: 108493 AN XY: 406982

African (AFR) AF: 0.101 AC: 1908 AN: 18946

American (AMR) AF: 0.409 AC: 14615 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 6784 AN: 20130

East Asian (EAS) AF: 0.387 AC: 13964 AN: 36086

South Asian (SAS) AF: 0.284 AC: 18740 AN: 66056

European-Finnish (FIN) AF: 0.237 AC: 12174 AN: 51322

Middle Eastern (MID) AF: 0.316 AC: 949 AN: 3002

European-Non Finnish (NFE) AF: 0.251 AC: 125714 AN: 500368

Other (OTH) AF: 0.261 AC: 9597 AN: 36762

GnomAD4 genome AF: 0.231 AC: 34889 AN: 150874 Hom.: 4698 Cov.: 30 AF XY: 0.235 AC XY: 17308 AN XY: 73718

African (AFR) AF: 0.103 AC: 4182 AN: 40682

American (AMR) AF: 0.352 AC: 5361 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1153 AN: 3462

East Asian (EAS) AF: 0.415 AC: 2128 AN: 5122

South Asian (SAS) AF: 0.280 AC: 1335 AN: 4772

European-Finnish (FIN) AF: 0.227 AC: 2376 AN: 10446

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17513 AN: 67860

Other (OTH) AF: 0.259 AC: 544 AN: 2102

Alfa AF: 0.260 Hom.: 6210

Bravo AF: 0.235

Asia WGS AF: 0.331 AC: 1147 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0010
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4766587; hg19: chr12-109685330; COSMIC: COSV58130562; COSMIC: COSV58130562;