12-120725928-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000017.4(ACADS):c.43A>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.711

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09180367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.43A>G	p.Arg15Gly	missense_variant	1/10	ENST00000242592.9
ACADS	NM_001302554.2	c.43A>G	p.Arg15Gly	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.43A>G	p.Arg15Gly	missense_variant	1/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2	c.43A>G	p.Arg15Gly	missense_variant	1/10	2
ACADS	ENST00000539690.1	n.155A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399912 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 693432

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 15 of the ACADS protein (p.Arg15Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ACADS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACADS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.73
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.092	T;T
MetaSVM	Uncertain	0.0096	D
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.78	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.27
Sift	Benign	0.29	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.47		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP		0.73
MPC		0.25
ClinPred		0.039	T
GERP RS		-2.5
Varity_R		0.084
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1338857285; hg19: chr12-121163731;