12-109235640-G-A

Variant names:

• chr12-109235640-G-A
• rs17848825
• NM_001093.4:c.4439G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	NM_001093.4	MANE Select	c.4439G>A	p.Arg1480Lys	missense	Exon 33 of 53	NP_001084.3
	ACACB	NM_001412734.1		c.4439G>A	p.Arg1480Lys	missense	Exon 34 of 54	NP_001399663.1
	ACACB	NM_001412735.1		c.4439G>A	p.Arg1480Lys	missense	Exon 33 of 53	NP_001399664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.4439G>A	p.Arg1480Lys	missense	Exon 33 of 53	ENSP00000341044.7
	ACACB	ENST00000377848.7	TSL:1	c.4439G>A	p.Arg1480Lys	missense	Exon 32 of 52	ENSP00000367079.3
	ACACB	ENST00000377854.9	TSL:5	c.437G>A	p.Arg146Lys	missense	Exon 32 of 47	ENSP00000367085.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.12	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.45		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
Mutation Taster		=56/44	polymorphism

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: rs17848825; hg19: chr12-109673445;