rs1373305585

Positions:

• chr12-120738596-C-G
• chr12-120738596-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000017.4(ACADS):​c.859C>G​(p.Leu287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADS	NM_000017.4	c.859C>G	p.Leu287Val	missense_variant	7/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.847C>G	p.Leu283Val	missense_variant	7/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.859C>G	p.Leu287Val	missense_variant	7/10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.847C>G	p.Leu283Val	missense_variant	7/10	2		ENSP00000401045.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250350 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460858 Hom.: 0 Cov.: 43 AF XY: 0.00000138 AC XY: 1 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.48	P;P
Vest4		0.72
MutPred		0.76		Loss of stability (P = 0.1838);.;
MVP		0.97
MPC		0.53
ClinPred		0.90	D
GERP RS		3.9
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1373305585; hg19: chr12-121176399;