12-109140043-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001093.4(ACACB):c.638G>A(p.Arg213His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,596,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ACACB NM_001093.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.264

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ACACB
• BP4: Computational evidence support a benign effect (MetaRNN=0.031434238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACB	NM_001093.4	c.638G>A	p.Arg213His	missense_variant	2/53	ENST00000338432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACB	ENST00000338432.12	c.638G>A	p.Arg213His	missense_variant	2/53	1	NM_001093.4	P1
ACACB	ENST00000377848.7	c.638G>A	p.Arg213His	missense_variant	1/52	1		P1
ACACB	ENST00000377854.9	c.-3365G>A		5_prime_UTR_variant	1/47	5
ACACB	ENST00000546328.1	n.65G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000511 AC: 12 AN: 234650 Hom.: 0 AF XY: 0.0000314 AC XY: 4 AN XY: 127514

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000208 AC: 30 AN: 1444452 Hom.: 0 Cov.: 34 AF XY: 0.0000237 AC XY: 17 AN XY: 718532

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000217

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74464

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.638G>A (p.R213H) alteration is located in exon 1 (coding exon 1) of the ACACB gene. This alteration results from a G to A substitution at nucleotide position 638, causing the arginine (R) at amino acid position 213 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.1
Dann	Benign	0.75
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0093	N
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.031
Sift	Benign	0.62	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;B
Vest4		0.045
MVP		0.014
MPC		0.29
ClinPred		0.011	T
GERP RS		-9.6
Varity_R		0.022
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs560908915; hg19: chr12-109577848;