12-109139539-A-G

Position:

chr12-109139539-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_001093.4(ACACB):c.134A>G(p.Gln45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,614,128 control chromosomes in the GnomAD database, including 18 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 17 hom. )

Consequence

ACACB
NM_001093.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0770

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.008687645).

BP6

Variant 12-109139539-A-G is Benign according to our data. Variant chr12-109139539-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 789325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr12-109139539-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACB	NM_001093.4 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	2/53	ENST00000338432.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACB	ENST00000338432.12 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	2/53	1	NM_001093.4	P1	O00763-1
ACACB	ENST00000377848.7 linkuse as main transcript	c.134A>G	p.Gln45Arg	missense_variant	1/52	1		P1	O00763-1
ACACB	ENST00000539864.1 linkuse as main transcript	c.59A>G	p.Gln20Arg	missense_variant	2/2	3
ACACB	ENST00000377854.9 linkuse as main transcript	c.-3869A>G		5_prime_UTR_variant	1/47	5

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

326

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00215

AC:

541

AN:

251482

Hom.:

AF XY:

0.00186

AC XY:

253

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00340

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00369

AC:

5398

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

2458

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00192

Gnomad4 ASJ exome

AF:

0.00574

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00443

Gnomad4 OTH exome

AF:

0.00334

GnomAD4 genome

AF:

0.00214

AC:

326

AN:

152234

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00721

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00331

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.00239

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00205

AC:

249

EpiCase

AF:

0.00262

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

ACACB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.3

DANN

Benign

0.78

DEOGEN2

Benign

0.35

T;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.45

.;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.0087

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.42

N;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.82

N;D;N

REVEL

Benign

0.17

Sift

Benign

0.39

T;T;T

Sift4G

Benign

1.0

T;D;T

Polyphen

0.0

B;.;B

Vest4

0.11

MVP

0.52

MPC

0.26

ClinPred

0.0045

GERP RS

0.15

Varity_R

0.050

gMVP

0.053

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over