chr17-37087350-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_198834.3(ACACA):c.7118G>A(p.Arg2373Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
ACACA
NM_198834.3 missense
NM_198834.3 missense
Scores
1
12
Clinical Significance
Conservation
PhyloP100: 4.10
Genes affected
ACACA (HGNC:84): (acetyl-CoA carboxylase alpha) 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. There are two ACC forms, alpha and beta, encoded by two different genes. ACC-alpha is highly enriched in lipogenic tissues. The enzyme is under long term control at the transcriptional and translational levels and under short term regulation by the phosphorylation/dephosphorylation of targeted serine residues and by allosteric transformation by citrate or palmitoyl-CoA. Multiple alternatively spliced transcript variants divergent in the 5' sequence and encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ACACA
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15404662).
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACACA | NM_198834.3 | c.7118G>A | p.Arg2373Gln | missense_variant | 56/56 | ENST00000616317.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACACA | ENST00000616317.5 | c.7118G>A | p.Arg2373Gln | missense_variant | 56/56 | 1 | NM_198834.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152050Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251418Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135874
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727240
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74248
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with ACACA-related conditions. This variant is present in population databases (rs773877053, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2336 of the ACACA protein (p.Arg2336Gln). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
Sift4G
Benign
T;T;T;T;T
Polyphen
B;B;B;.;.
Vest4
MutPred
0.35
.;.;Loss of phosphorylation at S2339 (P = 0.0589);.;.;
MVP
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at