chr12-109235640-G-A

Position:

• chr12-109235640-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001093.4(ACACB):​c.4439G>A​(p.Arg1480Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.94

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACACB. . Gene score misZ 1.5694 (greater than the threshold 3.09). Trascript score misZ 3.0917 (greater than threshold 3.09). GenCC has associacion of gene with isolated cleft palate.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACACB	NM_001093.4	c.4439G>A	p.Arg1480Lys	missense_variant	33/53	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.4439G>A	p.Arg1480Lys	missense_variant	33/53	1	NM_001093.4	ENSP00000341044.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.27
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.68
MutPred		0.45		Gain of ubiquitination at R1480 (P = 0.0146);.;Gain of ubiquitination at R1480 (P = 0.0146);
MVP		0.51
MPC		0.88
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs17848825; hg19: chr12-109673445;