rs1799958

Positions:

chr12-120738280-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000242592.9(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
ENST00000242592.9 missense, splice_region

Scores

Splicing: ADA: 0.9053

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11O:3

Conservation

PhyloP100: 9.56

Variant links:

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]

ACADS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	6/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2 linkuse as main transcript	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	6/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9 linkuse as main transcript	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	6/10	1	NM_000017.4	ENSP00000242592	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	6/10	2		ENSP00000401045

Frequencies

GnomAD3 genomes

AF:

0.211

AC:

32093

AN:

152008

Hom.:

4233

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.261

AC XY:

189472

AN XY:

727218

show subpopulations

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.:

AF XY:

0.218

AC XY:

16232

AN XY:

74346

show subpopulations

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:1Benign:11Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:1Benign:4Other:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -

not provided

Benign:4Other: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. -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	- -

not specified

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

D;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-2.0

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

3.1e-12

P;P

PrimateAI

Uncertain

0.69

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

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

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