17-37252940-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_198834.3(ACACA):c.1923G>A(p.Gln641=) variant causes a synonymous change. The variant allele was found at a frequency of 0.145 in 1,614,036 control chromosomes in the GnomAD database, including 21,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1879 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19864 hom.)
• Consequence: ACACA NM_198834.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 17-37252940-C-T is Benign according to our data. Variant chr17-37252940-C-T is described in ClinVar as [Benign]. Clinvar id is 559346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACACA	NM_198834.3	c.1923G>A	p.Gln641=	synonymous_variant	15/56	ENST00000616317.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACACA	ENST00000616317.5	c.1923G>A	p.Gln641=	synonymous_variant	15/56	1	NM_198834.3

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19451 AN: 152078 Hom.: 1877 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.181 AC: 45439 AN: 251476 Hom.: 5702 AF XY: 0.189 AC XY: 25749 AN XY: 135910

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.147 AC: 214602 AN: 1461840 Hom.: 19864 Cov.: 34 AF XY: 0.153 AC XY: 111011 AN XY: 727232

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.128 AC: 19467 AN: 152196 Hom.: 1879 Cov.: 32 AF XY: 0.138 AC XY: 10233 AN XY: 74402

Gnomad4 AFR AF: 0.0392

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.138

Alfa AF: 0.122 Hom.: 979

Bravo AF: 0.117

Asia WGS AF: 0.353 AC: 1226 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.130

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -

ACACA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

Acetyl-CoA: carboxylase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.5
Dann	Benign	0.72

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: rs2229416; hg19: chr17-35609866;