NM_001093.4:c.129G>A

Variant names:

• chr12-109139534-G-A
• rs146888683
• NM_001093.4:c.129G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001093.4(ACACB):​c.129G>A​(p.Pro43Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ACACB NM_001093.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.924
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-109139534-G-A is Benign according to our data. Variant chr12-109139534-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3038985.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.924 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	NM_001093.4	MANE Select	c.129G>A	p.Pro43Pro	synonymous	Exon 2 of 53	NP_001084.3	O00763-1
	ACACB	NM_001412734.1		c.129G>A	p.Pro43Pro	synonymous	Exon 3 of 54	NP_001399663.1	O00763-1
	ACACB	NM_001412735.1		c.129G>A	p.Pro43Pro	synonymous	Exon 2 of 53	NP_001399664.1	O00763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACACB	ENST00000338432.12	TSL:1 MANE Select	c.129G>A	p.Pro43Pro	synonymous	Exon 2 of 53	ENSP00000341044.7	O00763-1
	ACACB	ENST00000377848.7	TSL:1	c.129G>A	p.Pro43Pro	synonymous	Exon 1 of 52	ENSP00000367079.3	O00763-1
	ACACB	ENST00000539864.1	TSL:3	c.54G>A	p.Pro18Pro	synonymous	Exon 2 of 2	ENSP00000443494.1	F5H5C3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251480 AF XY: 0.0000515

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151940 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74192

African (AFR) AF: 0.00 AC: 0 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000450 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ACACB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.96
DANN	Benign	0.46
PhyloP100		-0.92
PromoterAI		-0.0080	Neutral

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: rs146888683; hg19: chr12-109577339;