rs1799958

chr12-120738280-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000017.4(ACADS):c.625G>A(p.Gly209Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,613,942 control chromosomes in the GnomAD database, including 54,922 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4239 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50683 hom.)
• Consequence: ACADS NM_000017.4 missense, splice_region
• Scores: Splicing: ADA: 0.9053
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10 O:3
• Conservation: PhyloP100: 9.56

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020888746).
• BP6: Variant 12-120738280-G-A is Benign according to our data. Variant chr12-120738280-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120738280-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	6/10	ENST00000242592.9
ACADS	NM_001302554.2	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	6/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	6/10	2

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32093 AN: 152008 Hom.: 4233 Cov.: 33

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.265 AC: 66490 AN: 251146 Hom.: 9719 AF XY: 0.267 AC XY: 36213 AN XY: 135784

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.294

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.258 AC: 377749 AN: 1461816 Hom.: 50683 Cov.: 74 AF XY: 0.261 AC XY: 189472 AN XY: 727218

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.264

GnomAD4 genome AF: 0.211 AC: 32101 AN: 152126 Hom.: 4239 Cov.: 33 AF XY: 0.218 AC XY: 16232 AN XY: 74346

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.312

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.253

Alfa AF: 0.254 Hom.: 9169

Bravo AF: 0.207

TwinsUK AF: 0.261 AC: 966

ALSPAC AF: 0.252 AC: 973

ESP6500AA AF: 0.0645 AC: 284

ESP6500EA AF: 0.265 AC: 2276

ExAC AF: 0.259 AC: 31447

Asia WGS AF: 0.237 AC: 822 AN: 3478

EpiCase AF: 0.279

EpiControl AF: 0.282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1 Benign:4 Other:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Benign and reported on 08-28-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-2.0	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	3.1e-12	P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.66	P;P
Vest4		0.32
MPC		0.34
ClinPred		0.032	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.61
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: rs1799958; hg19: chr12-121176083; COSMIC: COSV54367967; COSMIC: COSV54367967;