rs555404

Variant names:

• chr12-120738181-T-C
• rs555404
• NM_000017.4:c.625-99T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-120738181-T-C
• chr12-120738181-T-A
• chr12-120738181-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001302554.2(ACADS):​c.605T>C​(p.Leu202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,590,938 control chromosomes in the GnomAD database, including 180,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21279 hom., cov: 32)
  • Exomes 𝑓: 0.47 (159352 hom.)
• Consequence: ACADS NM_001302554.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.88
• Publications: 25 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 -19 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: 0.52376 (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=4.065955E-6).
• BP6: Variant 12-120738181-T-C is Benign according to our data. Variant chr12-120738181-T-C is described in ClinVar as Benign. ClinVar VariationId is 1188992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302554.2. 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.625-99T>C		intron	N/A	NP_000008.1	P16219
	ACADS	NM_001302554.2		c.605T>C	p.Leu202Pro	missense	Exon 5 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.625-99T>C		intron	N/A	ENSP00000242592.4	P16219
	ACADS	ENST00000411593.2	TSL:2	c.605T>C	p.Leu202Pro	missense	Exon 5 of 10	ENSP00000401045.2	E9PE82
	ACADS	ENST00000946559.1		c.625-99T>C		intron	N/A	ENSP00000616618.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79102 AN: 151788 Hom.: 21249 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.520 AC: 109704 AN: 210954 AF XY: 0.520

Gnomad AFR exome AF: 0.647

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.537

Gnomad FIN exome AF: 0.453

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.466 AC: 670092 AN: 1439032 Hom.: 159352 Cov.: 84 AF XY: 0.471 AC XY: 336306 AN XY: 714224

African (AFR) AF: 0.646 AC: 21179 AN: 32786

American (AMR) AF: 0.611 AC: 24873 AN: 40702

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12380 AN: 25736

East Asian (EAS) AF: 0.485 AC: 18556 AN: 38278

South Asian (SAS) AF: 0.645 AC: 54241 AN: 84076

European-Finnish (FIN) AF: 0.453 AC: 23128 AN: 51026

Middle Eastern (MID) AF: 0.617 AC: 3545 AN: 5748

European-Non Finnish (NFE) AF: 0.438 AC: 482765 AN: 1101082

Other (OTH) AF: 0.494 AC: 29425 AN: 59598

GnomAD4 genome AF: 0.521 AC: 79174 AN: 151906 Hom.: 21279 Cov.: 32 AF XY: 0.529 AC XY: 39258 AN XY: 74226

African (AFR) AF: 0.637 AC: 26399 AN: 41426

American (AMR) AF: 0.562 AC: 8578 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2781 AN: 5148

South Asian (SAS) AF: 0.638 AC: 3071 AN: 4812

European-Finnish (FIN) AF: 0.461 AC: 4871 AN: 10562

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30121 AN: 67926

Other (OTH) AF: 0.534 AC: 1123 AN: 2102

Alfa AF: 0.518 Hom.: 9867

Bravo AF: 0.531

TwinsUK AF: 0.441 AC: 1637

ALSPAC AF: 0.440 AC: 1694

ExAC AF: 0.492 AC: 58933

Asia WGS AF: 0.620 AC: 2155 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Deficiency of butyryl-CoA dehydrogenase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.21
DANN	Benign	0.63
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000041	T
MetaSVM	Benign	-0.96	T
PhyloP100		-2.9
PROVEAN	Benign	0.64	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.027
ClinPred		0.0046	T
GERP RS		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs555404; hg19: chr12-121175984; COSMIC: COSV54368147; COSMIC: COSV54368147;