rs1800556

Variant names:

• chr12-120737875-C-T
• rs1800556
• NM_000017.4:c.511C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000017.4(ACADS):​c.511C>T​(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,613,908 control chromosomes in the GnomAD database, including 1,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (103 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1492 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8 O:2
• Conservation: PhyloP100: 0.510
• Publications: 54 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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000017.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041048765).
• BP6: Variant 12-120737875-C-T is Benign according to our data. Variant chr12-120737875-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0316 (4805/152176) while in subpopulation NFE AF = 0.0442 (3005/67976). AF 95% confidence interval is 0.0429. There are 103 homozygotes in GnomAd4. There are 2345 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

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.511C>T	p.Arg171Trp	missense	Exon 5 of 10	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.473-174C>T		intron	N/A	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.511C>T	p.Arg171Trp	missense	Exon 5 of 10	ENSP00000242592.4	P16219
	ACADS	ENST00000946559.1		c.511C>T	p.Arg171Trp	missense	Exon 5 of 10	ENSP00000616618.1
	ACADS	ENST00000893619.1		c.511C>T	p.Arg171Trp	missense	Exon 5 of 10	ENSP00000563678.1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4806 AN: 152058 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0653

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0309 AC: 7750 AN: 250994 AF XY: 0.0310

Gnomad AFR exome AF: 0.00887

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0443

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0423 AC: 61903 AN: 1461732 Hom.: 1492 Cov.: 33 AF XY: 0.0414 AC XY: 30070 AN XY: 727170

African (AFR) AF: 0.00792 AC: 265 AN: 33478

American (AMR) AF: 0.0177 AC: 793 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 629 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00692 AC: 597 AN: 86258

European-Finnish (FIN) AF: 0.0625 AC: 3338 AN: 53378

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5768

European-Non Finnish (NFE) AF: 0.0485 AC: 53897 AN: 1111908

Other (OTH) AF: 0.0382 AC: 2304 AN: 60386

GnomAD4 genome AF: 0.0316 AC: 4805 AN: 152176 Hom.: 103 Cov.: 33 AF XY: 0.0315 AC XY: 2345 AN XY: 74386

African (AFR) AF: 0.00946 AC: 393 AN: 41540

American (AMR) AF: 0.0331 AC: 507 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.0653 AC: 691 AN: 10586

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0442 AC: 3005 AN: 67976

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.0376 Hom.: 492

Bravo AF: 0.0288

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0511 AC: 197

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0465 AC: 400

ExAC AF: 0.0312 AC: 3787

Asia WGS AF: 0.00606 AC: 23 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0398

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	6	Deficiency of butyryl-CoA dehydrogenase (9)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	-0.056
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.041	T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.51
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.29
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.037	D
Polyphen		0.99	D
Vest4		0.15
MPC		0.21
ClinPred		0.063	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.78
Mutation Taster		=75/25	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800556; hg19: chr12-121175678; COSMIC: COSV54369699; COSMIC: COSV54369699;