12-109180060-T-G

Variant names:

• chr12-109180060-T-G
• rs11065772
• NM_001093.4:c.1791T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001093.4(ACACB):​c.1791T>G​(p.Asp597Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACACB	NM_001093.4	c.1791T>G	p.Asp597Glu	missense_variant	Exon 11 of 53	ENST00000338432.12	NP_001084.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACACB	ENST00000338432.12	c.1791T>G	p.Asp597Glu	missense_variant	Exon 11 of 53	1	NM_001093.4	ENSP00000341044.7
ACACB	ENST00000377848.7	c.1791T>G	p.Asp597Glu	missense_variant	Exon 10 of 52	1		ENSP00000367079.3
ACACB	ENST00000377854	c.-2212T>G		5_prime_UTR_variant	Exon 10 of 47	5		ENSP00000367085.6
ACACB	ENST00000543080.1	n.*20T>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459902 Hom.: 0 Cov.: 63 AF XY: 0.00000138 AC XY: 1 AN XY: 726134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	5.9
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.59
Sift	Benign	0.058	T;T
Sift4G	Benign	0.35	T;T
Polyphen		1.0	D;D
Vest4		0.58
MutPred		0.61		Gain of catalytic residue at N599 (P = 0.0013);Gain of catalytic residue at N599 (P = 0.0013);
MVP		0.49
MPC		0.53
ClinPred		0.92	D
GERP RS		-6.3
Varity_R		0.67
gMVP		0.78

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: rs11065772; hg19: chr12-109617865;