NM_001093.4:c.4240-42C>T

Variant names:

• chr12-109233896-C-T
• rs7974040
• NM_001093.4:c.4240-42C>T

Variant summary

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

The NM_001093.4(ACACB):​c.4240-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,612,504 control chromosomes in the GnomAD database, including 39,532 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 0.20 (3308 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36224 hom.)
• Consequence: ACACB NM_001093.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• Publications: 12 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACACB	NM_001093.4	c.4240-42C>T		intron_variant	Intron 30 of 52	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.4240-42C>T		intron_variant	Intron 30 of 52	1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.4240-42C>T		intron_variant	Intron 29 of 51	1		ENSP00000367079.3
ACACB	ENST00000377854.9	c.238-42C>T		intron_variant	Intron 29 of 46	5		ENSP00000367085.6
ACACB	ENST00000538526.5	n.238-42C>T		intron_variant	Intron 2 of 25	5		ENSP00000443281.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30723 AN: 152050 Hom.: 3308 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.187 AC: 46926 AN: 250754 AF XY: 0.186

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.00920

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.217 AC: 317463 AN: 1460336 Hom.: 36224 Cov.: 33 AF XY: 0.215 AC XY: 156242 AN XY: 726484

African (AFR) AF: 0.196 AC: 6560 AN: 33440

American (AMR) AF: 0.175 AC: 7804 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6316 AN: 26132

East Asian (EAS) AF: 0.0131 AC: 519 AN: 39686

South Asian (SAS) AF: 0.131 AC: 11333 AN: 86230

European-Finnish (FIN) AF: 0.223 AC: 11908 AN: 53332

Middle Eastern (MID) AF: 0.154 AC: 889 AN: 5760

European-Non Finnish (NFE) AF: 0.234 AC: 259622 AN: 1110708

Other (OTH) AF: 0.207 AC: 12512 AN: 60344

GnomAD4 genome AF: 0.202 AC: 30738 AN: 152168 Hom.: 3308 Cov.: 32 AF XY: 0.198 AC XY: 14766 AN XY: 74396

African (AFR) AF: 0.199 AC: 8241 AN: 41510

American (AMR) AF: 0.187 AC: 2858 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 873 AN: 3470

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5182

South Asian (SAS) AF: 0.118 AC: 567 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2365 AN: 10600

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15205 AN: 67980

Other (OTH) AF: 0.186 AC: 393 AN: 2114

Alfa AF: 0.220 Hom.: 3373

Bravo AF: 0.199

Asia WGS AF: 0.0780 AC: 272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.72
PhyloP100		0.22
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

Other links and lift over

dbSNP: rs7974040; hg19: chr12-109671701; COSMIC: COSV58143994; COSMIC: COSV58143994;