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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G209C) has been classified as Uncertain significance.

• 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, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000017.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	NM_000017.4	MANE Select	c.625G>A	p.Gly209Ser	missense splice_region	Exon 6 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.613G>A	p.Gly205Ser	missense splice_region	Exon 6 of 10	NP_001289483.1	E9PE82

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADS	ENST00000242592.9	TSL:1 MANE Select	c.625G>A	p.Gly209Ser	missense splice_region	Exon 6 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.625G>A	p.Gly209Ser	missense splice_region	Exon 6 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.625G>A	p.Gly209Ser	missense splice_region	Exon 6 of 10	ENSP00000563678.1

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	4	Deficiency of butyryl-CoA dehydrogenase (7)
-	-	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-2.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.66	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
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;