rs1799958

Variant names:

• chr12-120738280-G-A
• rs1799958
• NM_000017.4:c.625G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PP2 PP3 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:12 O:3
• Conservation: PhyloP100: 9.56
• Publications: 103 publications found

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 Gene-Disease associations (from GenCC):

• short chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.58444 (below the threshold of 3.09). Trascript score misZ: 0.78549 (below the threshold of 3.09). GenCC associations: The gene is linked to short chain acyl-CoA dehydrogenase deficiency.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• 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 Benign/Likely_benign. ClinVar VariationId is 3831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	Exon 6 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.625G>A	p.Gly209Ser	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.613G>A	p.Gly205Ser	missense_variant, splice_region_variant	Exon 6 of 10	2		ENSP00000401045.2
ENSG00000255946	ENST00000724268.1	n.305-7992C>T		intron_variant	Intron 1 of 1

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

GnomAD2 exomes AF: 0.265 AC: 66490 AN: 251146 AF XY: 0.267

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 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

African (AFR) AF: 0.0577 AC: 1932 AN: 33480

American (AMR) AF: 0.361 AC: 16149 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8839 AN: 26136

East Asian (EAS) AF: 0.120 AC: 4757 AN: 39698

South Asian (SAS) AF: 0.293 AC: 25260 AN: 86258

European-Finnish (FIN) AF: 0.270 AC: 14397 AN: 53378

Middle Eastern (MID) AF: 0.368 AC: 2121 AN: 5766

European-Non Finnish (NFE) AF: 0.259 AC: 288350 AN: 1111988

Other (OTH) AF: 0.264 AC: 15944 AN: 60396

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

African (AFR) AF: 0.0658 AC: 2731 AN: 41528

American (AMR) AF: 0.312 AC: 4776 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3470

East Asian (EAS) AF: 0.123 AC: 633 AN: 5166

South Asian (SAS) AF: 0.276 AC: 1331 AN: 4826

European-Finnish (FIN) AF: 0.270 AC: 2859 AN: 10586

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17729 AN: 67952

Other (OTH) AF: 0.253 AC: 532 AN: 2106

Alfa AF: 0.245 Hom.: 13818

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:12 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not provided Benign:4 Other:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:3

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 16, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Aug 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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;.
PhyloP100		9.6
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
Vest4		0.32
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
Mutation Taster		=25/75	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799958; hg19: chr12-121176083; COSMIC: COSV54367967; COSMIC: COSV54367967;