rs541587321

Positions:

• chr12-120739194-C-G
• chr12-120739194-C-T

Variant summary

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

The NM_000017.4(ACADS):​c.1084C>G​(p.Gln362Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADS NM_000017.4 missense, splice_region
• Scores: Splicing: ADA: 0.2673
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADS	NM_000017.4	c.1084C>G	p.Gln362Glu	missense_variant, splice_region_variant	9/10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.1072C>G	p.Gln358Glu	missense_variant, splice_region_variant	9/10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.1084C>G	p.Gln362Glu	missense_variant, splice_region_variant	9/10	1	NM_000017.4	ENSP00000242592	P1
ACADS	ENST00000411593.2	c.1072C>G	p.Gln358Glu	missense_variant, splice_region_variant	9/10	2		ENSP00000401045

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 529838). This missense change has been observed in individual(s) with a positive newborn screening result for ACADS-related disease (PMID: 22424739; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 362 of the ACADS protein (p.Gln362Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.096
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-1.2	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.58	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.0060	B;P
Vest4		0.81
MutPred		0.57		Gain of disorder (P = 0.1435);.;
MVP		0.95
MPC		0.51
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.41
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: rs541587321; hg19: chr12-121176997;